{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T21:57:37Z","timestamp":1793224657307,"version":"4.5.0"},"reference-count":84,"publisher":"National Academy of Sciences","issue":"19","license":[{"start":{"date-parts":[[2020,4,24]],"date-time":"2020-04-24T00:00:00Z","timestamp":1587686400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["1R56DK119709-01"],"award-info":[{"award-number":["1R56DK119709-01"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R00 DK106655"],"award-info":[{"award-number":["R00 DK106655"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["1R01DK123463-01"],"award-info":[{"award-number":["1R01DK123463-01"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["P30DK11485"],"award-info":[{"award-number":["P30DK11485"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009257","name":"ASN Foundation for Kidney Research","doi-asserted-by":"publisher","award":["Carl W. Gottschalk Research Scholar Grant"],"award-info":[{"award-number":["Carl W. Gottschalk Research Scholar Grant"]}],"id":[{"id":"10.13039\/100009257","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01 DK110575"],"award-info":[{"award-number":["R01 DK110575"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","award":["W81XWH-17-1-0158"],"award-info":[{"award-number":["W81XWH-17-1-0158"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000875","name":"Pew Charitable Trusts","doi-asserted-by":"publisher","award":["Pew scholar award"],"award-info":[{"award-number":["Pew scholar award"]}],"id":[{"id":"10.13039\/100000875","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2020,5,12]]},"abstract":"<jats:p>\n                    Genetic variants in\n                    <jats:italic>PKD2<\/jats:italic>\n                    which encodes for the polycystin-2 ion channel are responsible for many clinical cases of autosomal dominant polycystic kidney disease (ADPKD). Despite our strong understanding of the genetic basis of ADPKD, we do not know how most variants impact channel function. Polycystin-2 is found in organelle membranes, including the primary cilium\u2014an antennae-like structure on the luminal side of the collecting duct. In this study, we focus on the structural and mechanistic regulation of polycystin-2 by its TOP domain\u2014a site with unknown function that is commonly altered by missense variants. We use direct cilia electrophysiology, cryogenic electron microscopy, and superresolution imaging to determine that variants of the TOP domain finger 1 motif destabilizes the channel structure and impairs channel opening without altering cilia localization and channel assembly. Our findings support the channelopathy classification of\n                    <jats:italic>PKD2<\/jats:italic>\n                    variants associated with ADPKD, where polycystin-2 channel dysregulation in the primary cilia may contribute to cystogenesis.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1920777117","type":"journal-article","created":{"date-parts":[[2020,4,24]],"date-time":"2020-04-24T20:06:11Z","timestamp":1587758771000},"page":"10329-10338","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":44,"title":["Molecular dysregulation of ciliary polycystin-2 channels caused by variants in the TOP domain"],"prefix":"10.1073","volume":"117","author":[{"given":"Thuy N.","family":"Vien","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6138-953X","authenticated-orcid":false,"given":"Jinliang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0492-5460","authenticated-orcid":false,"given":"Leo C. T.","family":"Ng","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erhu","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8776-983X","authenticated-orcid":false,"given":"Paul G.","family":"DeCaen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2020,4,24]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1016\/S0140-6736(07)60601-1","article-title":"Autosomal dominant polycystic kidney disease","volume":"369","author":"Torres V. E.","year":"2007","unstructured":"V. E. Torres, P. C. Harris, Y. Pirson, Autosomal dominant polycystic kidney disease. Lancet 369, 1287\u20131301 (2007).","journal-title":"Lancet"},{"key":"e_1_3_4_2_2","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1056\/NEJM199307293290508","article-title":"Autosomal dominant polycystic kidney disease","volume":"329","author":"Gabow P. A.","year":"1993","unstructured":"P. A. Gabow, Autosomal dominant polycystic kidney disease. N. Engl. J. Med. 329, 332\u2013342 (1993).","journal-title":"N. Engl. J. Med."},{"key":"e_1_3_4_3_2","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1126\/science.272.5266.1339","article-title":"PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein","volume":"272","author":"Mochizuki T.","year":"1996","unstructured":"T. Mochizuki ., PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science 272, 1339\u20131342 (1996).","journal-title":"Science"},{"key":"e_1_3_4_4_2","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1038\/ng0695-151","article-title":"The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains","volume":"10","author":"Hughes J.","year":"1995","unstructured":"J. Hughes ., The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains. Nat. Genet. 10, 151\u2013160 (1995).","journal-title":"Nat. Genet."},{"key":"e_1_3_4_5_2","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1093\/hmg\/8.3.509","article-title":"Germinal and somatic mutations in the PKD2 gene of renal cysts in autosomal dominant polycystic kidney disease","volume":"8","author":"Koptides M.","year":"1999","unstructured":"M. Koptides, C. Hadjimichael, P. Koupepidou, A. Pierides, C. Constantinou Deltas, Germinal and somatic mutations in the PKD2 gene of renal cysts in autosomal dominant polycystic kidney disease. Hum. Mol. Genet. 8, 509\u2013513 (1999).","journal-title":"Hum. Mol. Genet."},{"key":"e_1_3_4_6_2","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/s41572-018-0047-y","article-title":"Polycystic kidney disease","volume":"4","author":"Bergmann C.","year":"2018","unstructured":"C. Bergmann ., Polycystic kidney disease. Nat. Rev. Dis. Primers 4, 50 (2018).","journal-title":"Nat. Rev. Dis. Primers"},{"key":"e_1_3_4_7_2","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1146\/annurev.biochem.75.103004.142819","article-title":"TRP channels","volume":"76","author":"Venkatachalam K.","year":"2007","unstructured":"K. Venkatachalam, C. Montell, TRP channels. Annu. Rev. Biochem. 76, 387\u2013417 (2007).","journal-title":"Annu. Rev. Biochem."},{"key":"e_1_3_4_8_2","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1172\/JCI119147","article-title":"Loss of the polycystic kidney disease (PKD1) region of chromosome 16p13 in renal cyst cells supports a loss-of-function model for cyst pathogenesis","volume":"99","author":"Brasier J. L.","year":"1997","unstructured":"J. L. Brasier, E. P. Henske, Loss of the polycystic kidney disease (PKD1) region of chromosome 16p13 in renal cyst cells supports a loss-of-function model for cyst pathogenesis. J. Clin. Invest. 99, 194\u2013199 (1997).","journal-title":"J. Clin. Invest."},{"key":"e_1_3_4_9_2","doi-asserted-by":"crossref","first-page":"a028175","DOI":"10.1101\/cshperspect.a028175","article-title":"Primary cilia and mammalian hedgehog signaling","volume":"9","author":"Bangs F.","year":"2017","unstructured":"F. Bangs, K. V. Anderson, Primary cilia and mammalian hedgehog signaling. Cold Spring Harb. Perspect. Biol. 9, a028175 (2017).","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"e_1_3_4_10_2","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.ceb.2011.12.007","article-title":"Cilia functions in development","volume":"24","author":"Drummond I. A.","year":"2012","unstructured":"I. A. Drummond, Cilia functions in development. Curr. Opin. Cell Biol. 24, 24\u201330 (2012).","journal-title":"Curr. Opin. Cell Biol."},{"key":"e_1_3_4_11_2","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1242\/dev.050054","article-title":"Cilia in vertebrate development and disease","volume":"139","author":"Oh E. C.","year":"2012","unstructured":"E. C. Oh, N. Katsanis, Cilia in vertebrate development and disease. Development 139, 443\u2013448 (2012).","journal-title":"Development"},{"key":"e_1_3_4_12_2","doi-asserted-by":"crossref","first-page":"F96","DOI":"10.1152\/ajprenal.00272.2016","article-title":"The native TRPP2-dependent channel of murine renal primary cilia","volume":"312","author":"Kleene S. J.","year":"2017","unstructured":"S. J. Kleene, N. K. Kleene, The native TRPP2-dependent channel of murine renal primary cilia. Am. J. Physiol. Renal Physiol. 312, F96\u2013F108 (2017).","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"e_1_3_4_13_2","doi-asserted-by":"crossref","first-page":"e33183","DOI":"10.7554\/eLife.33183","article-title":"Polycystin-2 is an essential ion channel subunit in the primary cilium of the renal collecting duct epithelium","volume":"7","author":"Liu X.","year":"2018","unstructured":"X. Liu ., Polycystin-2 is an essential ion channel subunit in the primary cilium of the renal collecting duct epithelium. eLife 7, e33183 (2018).","journal-title":"eLife"},{"key":"e_1_3_4_14_2","doi-asserted-by":"crossref","first-page":"eaat9819","DOI":"10.1126\/science.aat9819","article-title":"Structure of the human PKD1-PKD2 complex","volume":"361","author":"Su Q.","year":"2018","unstructured":"Q. Su ., Structure of the human PKD1-PKD2 complex. Science 361, eaat9819 (2018).","journal-title":"Science"},{"key":"e_1_3_4_15_2","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1038\/nsmb.3357","article-title":"Molecular insights into lipid-assisted Ca2+ regulation of the TRP channel Polycystin-2","volume":"24","author":"Wilkes M.","year":"2017","unstructured":"M. Wilkes ., Molecular insights into lipid-assisted Ca2+ regulation of the TRP channel Polycystin-2. Nat. Struct. Mol. Biol. 24, 123\u2013130 (2017).","journal-title":"Nat. Struct. Mol. Biol."},{"key":"e_1_3_4_16_2","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1038\/nsmb.3343","article-title":"Structure of the polycystic kidney disease TRP channel Polycystin-2 (PC2)","volume":"24","author":"Grieben M.","year":"2017","unstructured":"M. Grieben ., Structure of the polycystic kidney disease TRP channel Polycystin-2 (PC2). Nat. Struct. Mol. Biol. 24, 114\u2013122 (2017).","journal-title":"Nat. Struct. Mol. Biol."},{"key":"e_1_3_4_17_2","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1016\/j.cell.2016.09.048","article-title":"The structure of the polycystic kidney disease channel PKD2 in lipid nanodiscs","volume":"167","author":"Shen P. S.","year":"2016","unstructured":"Shen, P. S. . The structure of the polycystic kidney disease channel PKD2 in lipid nanodiscs. Cell 167, 763\u2013773.e11 (2016).","journal-title":"Cell"},{"key":"e_1_3_4_18_2","doi-asserted-by":"crossref","first-page":"e48336","DOI":"10.15252\/embr.201948336","article-title":"The ion channel function of polycystin-1 in the polycystin-1\/polycystin-2 complex","volume":"20","author":"Wang Z.","year":"2019","unstructured":"Z. Wang ., The ion channel function of polycystin-1 in the polycystin-1\/polycystin-2 complex. EMBO Rep. 20, e48336 (2019).","journal-title":"EMBO Rep."},{"key":"e_1_3_4_19_2","doi-asserted-by":"crossref","first-page":"2143","DOI":"10.1681\/ASN.2006121387","article-title":"Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease","volume":"18","author":"Rossetti S.","year":"2007","unstructured":"S. Rossetti .; CRISP Consortium, Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease. J. Am. Soc. Nephrol. 18, 2143\u20132160 (2007).","journal-title":"J. Am. Soc. Nephrol."},{"key":"e_1_3_4_20_2","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/S0140-6736(98)03495-3","article-title":"Comparison of phenotypes of polycystic kidney disease types 1 and 2. European PKD1-PKD2 study group","volume":"353","author":"Hateboer N.","year":"1999","unstructured":"N. Hateboer ., Comparison of phenotypes of polycystic kidney disease types 1 and 2. European PKD1-PKD2 study group. Lancet 353, 103\u2013107 (1999).","journal-title":"Lancet"},{"key":"e_1_3_4_21_2","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/S0092-8674(00)81570-6","article-title":"Somatic inactivation of Pkd2 results in polycystic kidney disease","volume":"93","author":"Wu G.","year":"1998","unstructured":"G. Wu ., Somatic inactivation of Pkd2 results in polycystic kidney disease. Cell 93, 177\u2013188 (1998).","journal-title":"Cell"},{"key":"e_1_3_4_22_2","doi-asserted-by":"crossref","first-page":"2843","DOI":"10.1016\/j.ajpath.2015.06.014","article-title":"Human polycystin-2 transgene dose-dependently rescues ADPKD phenotypes in Pkd2 mutant mice","volume":"185","author":"Li A.","year":"2015","unstructured":"A. Li ., Human polycystin-2 transgene dose-dependently rescues ADPKD phenotypes in Pkd2 mutant mice. Am. J. Pathol. 185, 2843\u20132860 (2015).","journal-title":"Am. J. Pathol."},{"key":"e_1_3_4_23_2","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1038\/ncb754","article-title":"Polycystin-2 is an intracellular calcium release channel","volume":"4","author":"Koulen P.","year":"2002","unstructured":"P. Koulen ., Polycystin-2 is an intracellular calcium release channel. Nat. Cell Biol. 4, 191\u2013197 (2002).","journal-title":"Nat. Cell Biol."},{"key":"e_1_3_4_24_2","doi-asserted-by":"crossref","first-page":"7214","DOI":"10.1074\/jbc.M805890200","article-title":"Cyst formation in kidney via B-Raf signaling in the PKD2 transgenic mice","volume":"284","author":"Park E. Y.","year":"2009","unstructured":"E. Y. Park ., Cyst formation in kidney via B-Raf signaling in the PKD2 transgenic mice. J. Biol. Chem. 284, 7214\u20137222 (2009).","journal-title":"J. Biol. Chem."},{"key":"e_1_3_4_25_2","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1093\/ndt\/gfm763","article-title":"Overexpression of PKD2 in the mouse is associated with renal tubulopathy","volume":"23","author":"Burtey S.","year":"2008","unstructured":"S. Burtey ., Overexpression of PKD2 in the mouse is associated with renal tubulopathy. Nephrol. Dial. Transplant. 23, 1157\u20131165 (2008).","journal-title":"Nephrol. Dial. Transplant."},{"key":"e_1_3_4_26_2","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1002\/humu.20474","article-title":"PKDB: Polycystic Kidney Disease Mutation DatabaseA gene variant database for autosomal dominant polycystic kidney disease","volume":"28","author":"Gout A. M.","year":"2007","unstructured":"A. M. Gout, N. C. Martin, A. F. Brown, D. Ravine, PKDB: Polycystic Kidney Disease Mutation DatabaseA gene variant database for autosomal dominant polycystic kidney disease. Hum. Mutat. 28, 654\u2013659 (2007).","journal-title":"Hum. Mutat."},{"key":"e_1_3_4_27_2","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1038\/s41598-017-01146-z","article-title":"Role of the ion channel extracellular collar in AMPA receptor gating","volume":"7","author":"Yelshanskaya M. V.","year":"2017","unstructured":"M. V. Yelshanskaya, S. Mesbahi-Vasey, M. G. Kurnikova, A. I. Sobolevsky, Role of the ion channel extracellular collar in AMPA receptor gating. Sci. Rep. 7, 1050 (2017).","journal-title":"Sci. Rep."},{"key":"e_1_3_4_28_2","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1038\/nature23269","article-title":"The lysosomal potassium channel TMEM175 adopts a novel tetrameric architecture","volume":"547","author":"Lee C.","year":"2017","unstructured":"C. Lee ., The lysosomal potassium channel TMEM175 adopts a novel tetrameric architecture. Nature 547, 472\u2013475 (2017).","journal-title":"Nature"},{"key":"e_1_3_4_29_2","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1126\/science.1213808","article-title":"Crystal structure of the human K2P TRAAK, a lipid- and mechano-sensitive K+ ion channel","volume":"335","author":"Brohawn S. G.","year":"2012","unstructured":"S. G. Brohawn, J. del M\u00e1rmol, R. MacKinnon, Crystal structure of the human K2P TRAAK, a lipid- and mechano-sensitive K+ ion channel. Science 335, 436\u2013441 (2012).","journal-title":"Science"},{"key":"e_1_3_4_30_2","doi-asserted-by":"crossref","first-page":"3326","DOI":"10.1364\/BOE.5.003326","article-title":"Correlative multicolor 3D SIM and STORM microscopy","volume":"5","author":"Hamel V.","year":"2014","unstructured":"V. Hamel ., Correlative multicolor 3D SIM and STORM microscopy. Biomed. Opt. Express 5, 3326\u20133336 (2014).","journal-title":"Biomed. Opt. Express"},{"key":"e_1_3_4_31_2","first-page":"4297","article-title":"Heat shock induces rapid resorption of primary cilia","volume":"125","author":"Prodromou N. V.","year":"2012","unstructured":"N. V. Prodromou ., Heat shock induces rapid resorption of primary cilia. J. Cell Sci. 125, 4297\u20134305 (2012).","journal-title":"J. Cell Sci."},{"key":"e_1_3_4_32_2","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/S0091-679X(08)94007-3","article-title":"Primary cilia and the cell cycle","volume":"94","author":"Plotnikova O. V.","year":"2009","unstructured":"O. V. Plotnikova, E. N. Pugacheva, E. A. Golemis, Primary cilia and the cell cycle. Methods Cell Biol. 94, 137\u2013160 (2009).","journal-title":"Methods Cell Biol."},{"key":"e_1_3_4_33_2","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1038\/nature12832","article-title":"Direct recording and molecular identification of the calcium channel of primary cilia","volume":"504","author":"DeCaen P. G.","year":"2013","unstructured":"P. G. DeCaen, M. Delling, T. N. Vien, D. E. Clapham, Direct recording and molecular identification of the calcium channel of primary cilia. Nature 504, 315\u2013318 (2013).","journal-title":"Nature"},{"key":"e_1_3_4_34_2","doi-asserted-by":"crossref","first-page":"e36931","DOI":"10.7554\/eLife.36931","article-title":"Cryo-EM structure of the polycystin 2-l1 ion channel","volume":"7","author":"Hulse R. E.","year":"2018","unstructured":"R. E. Hulse, Z. Li, R. K. Huang, J. Zhang, D. E. Clapham, Cryo-EM structure of the polycystin 2-l1 ion channel. eLife 7, e36931 (2018).","journal-title":"eLife"},{"key":"e_1_3_4_35_2","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1038\/s41467-018-03606-0","article-title":"Cryo-EM structure of the polycystic kidney disease-like channel PKD2L1","volume":"9","author":"Su Q.","year":"2018","unstructured":"Q. Su ., Cryo-EM structure of the polycystic kidney disease-like channel PKD2L1. Nat. Commun. 9, 1192 (2018).","journal-title":"Nat. Commun."},{"key":"e_1_3_4_36_2","doi-asserted-by":"crossref","first-page":"E2363","DOI":"10.1073\/pnas.1517066113","article-title":"Function and regulation of TRPP2 ion channel revealed by a gain-of-function mutant","volume":"113","author":"Arif Pavel M.","year":"2016","unstructured":"M. Arif Pavel ., Function and regulation of TRPP2 ion channel revealed by a gain-of-function mutant. Proc. Natl. Acad. Sci. U.S.A. 113, E2363\u2013E2372 (2016).","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"e_1_3_4_37_2","volume-title":"Ion Channels of Excitable Membranes","author":"Hille B.","year":"2001","unstructured":"B. Hille, Ion Channels of Excitable Membranes (Sinauer, ed. 3, 2001).","edition":"3"},{"key":"e_1_3_4_38_2","doi-asserted-by":"crossref","first-page":"1986","DOI":"10.1172\/JCI26011","article-title":"The channelopathies: Novel insights into molecular and genetic mechanisms of human disease","volume":"115","author":"Kass R. S.","year":"2005","unstructured":"R. S. Kass, The channelopathies: Novel insights into molecular and genetic mechanisms of human disease. J. Clin. Invest. 115, 1986\u20131989 (2005).","journal-title":"J. Clin. Invest."},{"key":"e_1_3_4_39_2","doi-asserted-by":"crossref","first-page":"121","DOI":"10.3389\/fphar.2016.00121","article-title":"Therapeutic approaches to genetic ion channelopathies and perspectives in drug discovery","volume":"7","author":"Imbrici P.","year":"2016","unstructured":"P. Imbrici ., Therapeutic approaches to genetic ion channelopathies and perspectives in drug discovery. Front. Pharmacol. 7, 121 (2016).","journal-title":"Front. Pharmacol."},{"key":"e_1_3_4_40_2","doi-asserted-by":"crossref","first-page":"1990","DOI":"10.1172\/JCI25505","article-title":"Inherited disorders of voltage-gated sodium channels","volume":"115","author":"George A. L.","year":"2005","unstructured":"A. L. George, Jr, Inherited disorders of voltage-gated sodium channels. J. Clin. Invest. 115, 1990\u20131999 (2005).","journal-title":"J. Clin. Invest."},{"key":"e_1_3_4_41_2","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1038\/ki.2008.686","article-title":"Incompletely penetrant PKD1 alleles suggest a role for gene dosage in cyst initiation in polycystic kidney disease","volume":"75","author":"Rossetti S.","year":"2009","unstructured":"S. Rossetti ., Incompletely penetrant PKD1 alleles suggest a role for gene dosage in cyst initiation in polycystic kidney disease. Kidney Int. 75, 848\u2013855 (2009). Correction to: Kidney Int. 77, 368 (2010).","journal-title":"Kidney Int."},{"key":"e_1_3_4_42_2","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1038\/nrd2983","article-title":"Voltage-gated potassium channels as therapeutic targets","volume":"8","author":"Wulff H.","year":"2009","unstructured":"H. Wulff, N. A. Castle, L. A. Pardo, Voltage-gated potassium channels as therapeutic targets. Nat. Rev. Drug Discov. 8, 982\u20131001 (2009).","journal-title":"Nat. Rev. Drug Discov."},{"key":"e_1_3_4_43_2","doi-asserted-by":"crossref","first-page":"7093","DOI":"10.1021\/jm501981g","article-title":"Voltage-gated sodium channels: Structure, function, pharmacology, and clinical indications","volume":"58","author":"de Lera Ruiz M.","year":"2015","unstructured":"M. de Lera Ruiz, R. L. Kraus, Voltage-gated sodium channels: Structure, function, pharmacology, and clinical indications. J. Med. Chem. 58, 7093\u20137118 (2015).","journal-title":"J. Med. Chem."},{"key":"e_1_3_4_44_2","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1016\/S0896-6273(00)80307-4","article-title":"Mapping the receptor site for hanatoxin, a gating modifier of voltage-dependent K+ channels","volume":"18","author":"Swartz K. J.","year":"1997","unstructured":"K. J. Swartz, R. MacKinnon, Mapping the receptor site for hanatoxin, a gating modifier of voltage-dependent K+ channels. Neuron 18, 675\u2013682 (1997).","journal-title":"Neuron"},{"key":"e_1_3_4_45_2","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.tips.2009.12.007","article-title":"Targeting voltage sensors in sodium channels with spider toxins","volume":"31","author":"Bosmans F.","year":"2010","unstructured":"F. Bosmans, K. J. Swartz, Targeting voltage sensors in sodium channels with spider toxins. Trends Pharmacol. Sci. 31, 175\u2013182 (2010).","journal-title":"Trends Pharmacol. Sci."},{"key":"e_1_3_4_46_2","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1056\/NEJMra1010172","article-title":"Ciliopathies","volume":"364","author":"Hildebrandt F.","year":"2011","unstructured":"F. Hildebrandt, T. Benzing, N. Katsanis, Ciliopathies. N. Engl. J. Med. 364, 1533\u20131543 (2011).","journal-title":"N. Engl. J. Med."},{"key":"e_1_3_4_47_2","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1007\/s00467-012-2259-9","article-title":"Current insights into renal ciliopathies: What can genetics teach us?","volume":"28","author":"Arts H. H.","year":"2013","unstructured":"H. H. Arts, N. V. Knoers, Current insights into renal ciliopathies: What can genetics teach us? Pediatr. Nephrol. 28, 863\u2013874 (2013).","journal-title":"Pediatr. Nephrol."},{"key":"e_1_3_4_48_2","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.neuropharm.2017.06.029","article-title":"Relevance of tissue specific subunit expression in channelopathies","volume":"132","author":"Seitter H.","year":"2018","unstructured":"H. Seitter, A. Koschak, Relevance of tissue specific subunit expression in channelopathies. Neuropharmacology 132, 58\u201370 (2018).","journal-title":"Neuropharmacology"},{"key":"e_1_3_4_49_2","doi-asserted-by":"crossref","first-page":"e74203","DOI":"10.1371\/journal.pone.0074203","article-title":"Rare variants in calcium homeostasis modulator 1 (CALHM1) found in early onset Alzheimer\u2019s disease patients alter calcium homeostasis","volume":"8","author":"Rubio-Moscardo F.","year":"2013","unstructured":"F. Rubio-Moscardo ., Rare variants in calcium homeostasis modulator 1 (CALHM1) found in early onset Alzheimer\u2019s disease patients alter calcium homeostasis. PLoS One 8, e74203 (2013).","journal-title":"PLoS One"},{"key":"e_1_3_4_50_2","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1038\/nature12833","article-title":"Primary cilia are specialized calcium signalling organelles","volume":"504","author":"Delling M.","year":"2013","unstructured":"M. Delling, P. G. DeCaen, J. F. Doerner, S. Febvay, D. E. Clapham, Primary cilia are specialized calcium signalling organelles. Nature 504, 311\u2013314 (2013).","journal-title":"Nature"},{"key":"e_1_3_4_51_2","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1038\/nature17426","article-title":"Primary cilia are not calcium-responsive mechanosensors","volume":"531","author":"Delling M.","year":"2016","unstructured":"M. Delling ., Primary cilia are not calcium-responsive mechanosensors. Nature 531, 656\u2013660 (2016).","journal-title":"Nature"},{"key":"e_1_3_4_52_2","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1085\/jgp.201611696","article-title":"Progress in ciliary ion channel physiology","volume":"149","author":"Pablo J. L.","year":"2017","unstructured":"J. L. Pablo, P. G. DeCaen, D. E. Clapham, Progress in ciliary ion channel physiology. J. Gen. Physiol. 149, 37\u201347 (2017).","journal-title":"J. Gen. Physiol."},{"key":"e_1_3_4_53_2","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1083\/jcb.201004108","article-title":"A mechanism for vertebrate hedgehog signaling: Recruitment to cilia and dissociation of SuFu-gli protein complexes","volume":"191","author":"Tukachinsky H.","year":"2010","unstructured":"H. Tukachinsky, L. V. Lopez, A. Salic, A mechanism for vertebrate hedgehog signaling: Recruitment to cilia and dissociation of SuFu-gli protein complexes. J. Cell Biol. 191, 415\u2013428 (2010).","journal-title":"J. Cell Biol."},{"key":"e_1_3_4_54_2","first-page":"2928","article-title":"Ciliary adenylyl cyclases control the Hedgehog pathway","volume":"128","author":"Vuolo L.","year":"2015","unstructured":"L. Vuolo, A. Herrera, B. Torroba, A. Menendez, S. Pons, Ciliary adenylyl cyclases control the Hedgehog pathway. J. Cell Sci. 128, 2928\u20132937 (2015).","journal-title":"J. Cell Sci."},{"key":"e_1_3_4_55_2","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.jsb.2015.08.008","article-title":"CTFFIND4: Fast and accurate defocus estimation from electron micrographs","volume":"192","author":"Rohou A.","year":"2015","unstructured":"A. Rohou, N. Grigorieff, CTFFIND4: Fast and accurate defocus estimation from electron micrographs. J. Struct. Biol. 192, 216\u2013221 (2015).","journal-title":"J. Struct. Biol."},{"key":"e_1_3_4_56_2","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/j.jsb.2012.09.006","article-title":"RELION: Implementation of a Bayesian approach to cryo-EM structure determination","volume":"180","author":"Scheres S. H.","year":"2012","unstructured":"S. H. Scheres, RELION: Implementation of a Bayesian approach to cryo-EM structure determination. J. Struct. Biol. 180, 519\u2013530 (2012).","journal-title":"J. Struct. Biol."},{"key":"e_1_3_4_57_2","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1006\/bbrc.2001.4554","article-title":"Polycystin-2 is a novel cation channel implicated in defective intracellular Ca(2+) homeostasis in polycystic kidney disease","volume":"282","author":"Vassilev P. M.","year":"2001","unstructured":"P. M. Vassilev ., Polycystin-2 is a novel cation channel implicated in defective intracellular Ca(2+) homeostasis in polycystic kidney disease. Biochem. Biophys. Res. Commun. 282, 341\u2013350 (2001).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"e_1_3_4_58_2","doi-asserted-by":"crossref","first-page":"1875","DOI":"10.1093\/hmg\/ddg190","article-title":"Pkd2 haploinsufficiency alters intracellular calcium regulation in vascular smooth muscle cells","volume":"12","author":"Qian Q.","year":"2003","unstructured":"Q. Qian ., Pkd2 haploinsufficiency alters intracellular calcium regulation in vascular smooth muscle cells. Hum. Mol. Genet. 12, 1875\u20131880 (2003).","journal-title":"Hum. Mol. Genet."},{"key":"e_1_3_4_59_2","doi-asserted-by":"crossref","first-page":"18794","DOI":"10.1074\/jbc.M109.090662","article-title":"Polycystin-2 activation by inositol 1,4,5-trisphosphate-induced Ca2+ release requires its direct association with the inositol 1,4,5-trisphosphate receptor in a signaling microdomain","volume":"285","author":"Sammels E.","year":"2010","unstructured":"E. Sammels ., Polycystin-2 activation by inositol 1,4,5-trisphosphate-induced Ca2+ release requires its direct association with the inositol 1,4,5-trisphosphate receptor in a signaling microdomain. J. Biol. Chem. 285, 18794\u201318805 (2010).","journal-title":"J. Biol. Chem."},{"key":"e_1_3_4_60_2","doi-asserted-by":"crossref","first-page":"41298","DOI":"10.1074\/jbc.M510082200","article-title":"Polycystin 2 interacts with type I inositol 1,4,5-trisphosphate receptor to modulate intracellular Ca2+ signaling","volume":"280","author":"Li Y.","year":"2005","unstructured":"Y. Li, J. M. Wright, F. Qian, G. G. Germino, W. B. Guggino, Polycystin 2 interacts with type I inositol 1,4,5-trisphosphate receptor to modulate intracellular Ca2+ signaling. J. Biol. Chem. 280, 41298\u201341306 (2005).","journal-title":"J. Biol. Chem."},{"key":"e_1_3_4_61_2","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1083\/jcb.200510084","article-title":"Nonvesicular sterol movement from plasma membrane to ER requires oxysterol-binding protein-related proteins and phosphoinositides","volume":"173","author":"Raychaudhuri S.","year":"2006","unstructured":"S. Raychaudhuri, Y. J. Im, J. H. Hurley, W. A. Prinz, Nonvesicular sterol movement from plasma membrane to ER requires oxysterol-binding protein-related proteins and phosphoinositides. J. Cell Biol. 173, 107\u2013119 (2006).","journal-title":"J. Cell Biol."},{"key":"e_1_3_4_62_2","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/nrm2330","article-title":"Membrane lipids: Where they are and how they behave","volume":"9","author":"van Meer G.","year":"2008","unstructured":"G. van Meer, D. R. Voelker, G. W. Feigenson, Membrane lipids: Where they are and how they behave. Nat. Rev. Mol. Cell Biol. 9, 112\u2013124 (2008).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"e_1_3_4_63_2","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/j.cell.2016.12.032","article-title":"Dynamic remodeling of membrane composition drives cell cycle through primary cilia excision","volume":"168","author":"Phua S. C.","year":"2017","unstructured":"S. C. Phua ., Dynamic remodeling of membrane composition drives cell cycle through primary cilia excision. Cell 168, 264\u2013279.e15 (2017).","journal-title":"Cell"},{"key":"e_1_3_4_64_2","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/j.devcel.2015.08.001","article-title":"Phosphoinositides regulate ciliary protein trafficking to modulate hedgehog signaling","volume":"34","author":"Garcia-Gonzalo F. R.","year":"2015","unstructured":"F. R. Garcia-Gonzalo ., Phosphoinositides regulate ciliary protein trafficking to modulate hedgehog signaling. Dev. Cell 34, 400\u2013409 (2015).","journal-title":"Dev. Cell"},{"key":"e_1_3_4_65_2","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1016\/j.bbamem.2012.01.014","article-title":"Comparing ion conductance recordings of synthetic lipid bilayers with cell membranes containing TRP channels","volume":"1818","author":"Laub K. R.","year":"2012","unstructured":"K. R. Laub ., Comparing ion conductance recordings of synthetic lipid bilayers with cell membranes containing TRP channels. Biochim. Biophys. Acta 1818, 1123\u20131134 (2012).","journal-title":"Biochim. Biophys. Acta"},{"key":"e_1_3_4_66_2","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1085\/jgp.201411336","article-title":"Transient receptor potential melastatin 3 is a phosphoinositide-dependent ion channel","volume":"146","author":"Badheka D.","year":"2015","unstructured":"D. Badheka, I. Borbiro, T. Rohacs, Transient receptor potential melastatin 3 is a phosphoinositide-dependent ion channel. J. Gen. Physiol. 146, 65\u201377 (2015).","journal-title":"J. Gen. Physiol."},{"key":"e_1_3_4_67_2","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1161\/01.CIR.21.5.879","article-title":"Measurements of electrical potentials and ion fluxes on single renal tubules","volume":"21","author":"Giebisch G.","year":"1960","unstructured":"G. Giebisch, Measurements of electrical potentials and ion fluxes on single renal tubules. Circulation 21, 879\u2013891 (1960).","journal-title":"Circulation"},{"key":"e_1_3_4_68_2","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1126\/science.1523409","article-title":"Oxidized redox state of glutathione in the endoplasmic reticulum","volume":"257","author":"Hwang C.","year":"1992","unstructured":"C. Hwang, A. J. Sinskey, H. F. Lodish, Oxidized redox state of glutathione in the endoplasmic reticulum. Science 257, 1496\u20131502 (1992).","journal-title":"Science"},{"key":"e_1_3_4_69_2","first-page":"1604","article-title":"Endoplasmic reticulum: Reduced and oxidized glutathione revisited","volume":"126","author":"Birk J.","year":"2013","unstructured":"J. Birk ., Endoplasmic reticulum: Reduced and oxidized glutathione revisited. J. Cell Sci. 126, 1604\u20131617 (2013).","journal-title":"J. Cell Sci."},{"key":"e_1_3_4_70_2","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1007\/BF02426954","article-title":"Glutathione is an essential metabolite required for resistance to oxidative stress in the yeast Saccharomyces cerevisiae","volume":"29","author":"Grant C. M.","year":"1996","unstructured":"C. M. Grant, F. H. MacIver, I. W. Dawes, Glutathione is an essential metabolite required for resistance to oxidative stress in the yeast Saccharomyces cerevisiae. Curr. Genet. 29, 511\u2013515 (1996).","journal-title":"Curr. Genet."},{"key":"e_1_3_4_71_2","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1016\/j.bbagen.2008.01.011","article-title":"Redox compartmentalization in eukaryotic cells","volume":"1780","author":"Go Y. M.","year":"2008","unstructured":"Y. M. Go, D. P. Jones, Redox compartmentalization in eukaryotic cells. Biochim. Biophys. Acta 1780, 1273\u20131290 (2008).","journal-title":"Biochim. Biophys. Acta"},{"key":"e_1_3_4_72_2","doi-asserted-by":"crossref","first-page":"1943","DOI":"10.1016\/j.freeradbiomed.2011.08.035","article-title":"Measuring E(GSH) and H2O2 with roGFP2-based redox probes","volume":"51","author":"Morgan B.","year":"2011","unstructured":"B. Morgan, M. C. Sobotta, T. P. Dick, Measuring E(GSH) and H2O2 with roGFP2-based redox probes. Free Radic. Biol. Med. 51, 1943\u20131951 (2011).","journal-title":"Free Radic. Biol. Med."},{"key":"e_1_3_4_73_2","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.ab.2006.01.047","article-title":"Fluorescence-based detection of thiols in vitro and in vivo using dithiol probes","volume":"352","author":"Pullela P. K.","year":"2006","unstructured":"P. K. Pullela, T. Chiku, M. J. Carvan, 3rd, D. S. Sem, Fluorescence-based detection of thiols in vitro and in vivo using dithiol probes. Anal. Biochem. 352, 265\u2013273 (2006).","journal-title":"Anal. Biochem."},{"key":"e_1_3_4_74_2","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1039\/c3mt00031a","article-title":"Effects of metal ions and disulfide bonds on the activity of phosphodiesterase from Trimeresurus stejnegeri venom","volume":"5","author":"Peng L.","year":"2013","unstructured":"L. Peng ., Effects of metal ions and disulfide bonds on the activity of phosphodiesterase from Trimeresurus stejnegeri venom. Metallomics 5, 920\u2013927, (2013).","journal-title":"Metallomics"},{"key":"e_1_3_4_75_2","doi-asserted-by":"crossref","first-page":"eaat7397","DOI":"10.1126\/scisignal.aat7397","article-title":"Polycystin 2 regulates mitochondrial Ca2+ signaling, bioenergetics, and dynamics through mitofusin 2","volume":"12","author":"Kuo I. Y.","year":"2019","unstructured":"I. Y. Kuo ., Polycystin 2 regulates mitochondrial Ca2+ signaling, bioenergetics, and dynamics through mitofusin 2. Sci. Signal. 12, eaat7397 (2019).","journal-title":"Sci. Signal."},{"key":"e_1_3_4_76_2","doi-asserted-by":"crossref","first-page":"36","DOI":"10.3389\/fcvm.2016.00036","article-title":"Mitochondrial ROS versus ER ROS: Which comes first in myocardial calcium dysregulation?","volume":"3","author":"Chaube R.","year":"2016","unstructured":"R. Chaube, G. H. Werstuck, Mitochondrial ROS versus ER ROS: Which comes first in myocardial calcium dysregulation? Front. Cardiovasc. Med. 3, 36 (2016).","journal-title":"Front. Cardiovasc. Med."},{"key":"e_1_3_4_77_2","doi-asserted-by":"crossref","first-page":"3440","DOI":"10.1016\/S0021-9258(19)83641-4","article-title":"A new generation of Ca2+ indicators with greatly improved fluorescence properties","volume":"260","author":"Grynkiewicz G.","year":"1985","unstructured":"G. Grynkiewicz, M. Poenie, R. Y. Tsien, A new generation of Ca2+ indicators with greatly improved fluorescence properties. J. Biol. Chem. 260, 3440\u20133450 (1985).","journal-title":"J. Biol. Chem."},{"key":"e_1_3_4_78_2","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/S0304-3991(99)00043-1","article-title":"Leginon: A system for fully automated acquisition of 1000 electron micrographs a day","volume":"77","author":"Potter C. S.","year":"1999","unstructured":"C. S. Potter ., Leginon: A system for fully automated acquisition of 1000 electron micrographs a day. Ultramicroscopy 77, 153\u2013161 (1999).","journal-title":"Ultramicroscopy"},{"key":"e_1_3_4_79_2","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.jsb.2005.07.007","article-title":"Automated electron microscope tomography using robust prediction of specimen movements","volume":"152","author":"Mastronarde D. N.","year":"2005","unstructured":"D. N. Mastronarde, Automated electron microscope tomography using robust prediction of specimen movements. J. Struct. Biol. 152, 36\u201351 (2005).","journal-title":"J. Struct. Biol."},{"key":"e_1_3_4_80_2","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1038\/nmeth.4193","article-title":"MotionCor2: Anisotropic correction of beam-induced motion for improved cryo-electron microscopy","volume":"14","author":"Zheng S. Q.","year":"2017","unstructured":"S. Q. Zheng ., MotionCor2: Anisotropic correction of beam-induced motion for improved cryo-electron microscopy. Nat. Methods 14, 331\u2013332 (2017).","journal-title":"Nat. Methods"},{"key":"e_1_3_4_81_2","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1107\/S0907444910007493","article-title":"Features and development of Coot","volume":"66","author":"Emsley P.","year":"2010","unstructured":"P. Emsley, B. Lohkamp, W. G. Scott, K. Cowtan, Features and development of Coot. Acta Crystallogr. D Biol. Crystallogr. 66, 486\u2013501 (2010).","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"e_1_3_4_82_2","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1107\/S0021889812017293","article-title":"Graphical tools for macromolecular crystallography in PHENIX","volume":"45","author":"Echols N.","year":"2012","unstructured":"N. Echols ., Graphical tools for macromolecular crystallography in PHENIX. J. Appl. Cryst. 45, 581\u2013586 (2012).","journal-title":"J. Appl. Cryst."},{"key":"e_1_3_4_83_2","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1002\/pro.3330","article-title":"MolProbity: More and better reference data for improved all-atom structure validation","volume":"27","author":"Williams C. J.","year":"2018","unstructured":"C. J. Williams ., MolProbity: More and better reference data for improved all-atom structure validation. Protein sci. 27, 293\u2013315, (2018).","journal-title":"Protein sci."},{"key":"e_1_3_4_84_2","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF ChimeraA visualization system for exploratory research and analysis","volume":"25","author":"Pettersen E. F.","year":"2004","unstructured":"E. F. Pettersen ., UCSF ChimeraA visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605\u20131612 (2004).","journal-title":"J. Comput. Chem."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.pnas.org\/syndication\/doi\/10.1073\/pnas.1920777117","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1920777117","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,7]],"date-time":"2022-06-07T17:25:36Z","timestamp":1654622736000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1920777117"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,24]]},"references-count":84,"journal-issue":{"issue":"19","published-print":{"date-parts":[[2020,5,12]]}},"alternative-id":["10.1073\/pnas.1920777117"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1920777117","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,24]]},"assertion":[{"value":"2020-04-24","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}