{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T10:51:59Z","timestamp":1789901519063,"version":"4.0.1"},"reference-count":70,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2024,4,11]],"date-time":"2024-04-11T00:00:00Z","timestamp":1712793600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,4,11]],"date-time":"2024-04-11T00:00:00Z","timestamp":1712793600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["23307-G0001-10013397-101"],"award-info":[{"award-number":["23307-G0001-10013397-101"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32330052"],"award-info":[{"award-number":["32330052"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Beijing Frontier Research Center for Biological Structure"},{"DOI":"10.13039\/501100000854","name":"Human Frontier Science Program","doi-asserted-by":"publisher","award":["LT000754"],"award-info":[{"award-number":["LT000754"]}],"id":[{"id":"10.13039\/501100000854","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Res"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The Ca<jats:sub>v<\/jats:sub>3.2 subtype of T-type calcium channels has been targeted for developing analgesics and anti-epileptics\u00a0for its role in pain\u00a0and epilepsy. Here we present the cryo-EM structures of Ca<jats:sub>v<\/jats:sub>3.2 alone and in complex with four T-type calcium channel selective antagonists with overall resolutions ranging from 2.8\u2009\u00c5 to 3.2\u2009\u00c5. The four compounds display two binding poses. ACT-709478 and TTA-A2 both place their cyclopropylphenyl-containing ends in the central cavity to directly obstruct ion flow, meanwhile extending their polar tails into the IV-I fenestration. TTA-P2 and ML218 project their 3,5-dichlorobenzamide groups into the II-III fenestration and place their hydrophobic tails in the cavity to impede ion permeation. The fenestration-penetrating mode immediately affords an explanation for the state-dependent activities of these antagonists. Structure-guided mutational analysis identifies several key residues that determine the T-type preference of these drugs. The structures also suggest the role of an endogenous lipid in stabilizing drug binding in the central cavity.<\/jats:p>","DOI":"10.1038\/s41422-024-00959-8","type":"journal-article","created":{"date-parts":[[2024,4,11]],"date-time":"2024-04-11T10:02:32Z","timestamp":1712829752000},"page":"440-450","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Structural basis for human Cav3.2 inhibition by selective antagonists"],"prefix":"10.1038","volume":"34","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6861-0425","authenticated-orcid":false,"given":"Jian","family":"Huang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueqin","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Lyu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinmeng","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaofeng","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ama\u00ebl","family":"Davakan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Lory","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4829-7416","authenticated-orcid":false,"given":"Nieng","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,4,11]]},"reference":[{"key":"959_CR1","doi-asserted-by":"publisher","first-page":"a003947","DOI":"10.1101\/cshperspect.a003947","volume":"3","author":"WA Catterall","year":"2011","unstructured":"Catterall, W. A. Voltage-gated calcium channels. Cold Spring Harb. Perspect. Biol. 3, a003947 (2011).","journal-title":"Cold Spring Harb. Perspect. Biol."},{"issue":"1","key":"959_CR2","first-page":"S56","volume":"147","author":"AC Dolphin","year":"2006","unstructured":"Dolphin, A. C. A short history of voltage-gated calcium channels. Br. J. Pharmacol. 147(1), S56\u2013S62 (2006).","journal-title":"Br. J. Pharmacol."},{"key":"959_CR3","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1152\/physrev.1994.74.2.365","volume":"74","author":"TF McDonald","year":"1994","unstructured":"McDonald, T. F., Pelzer, S., Trautwein, W. & Pelzer, D. J. Regulation and modulation of calcium channels in cardiac, skeletal, and smooth muscle cells. Physiol. Rev. 74, 365\u2013507 (1994).","journal-title":"Physiol. Rev."},{"key":"959_CR4","doi-asserted-by":"publisher","first-page":"1047","DOI":"10.1016\/j.cell.2007.11.028","volume":"131","author":"DE Clapham","year":"2007","unstructured":"Clapham, D. E. Calcium signaling. Cell 131, 1047\u20131058 (2007).","journal-title":"Cell"},{"key":"959_CR5","doi-asserted-by":"publisher","first-page":"5478","DOI":"10.1073\/pnas.84.15.5478","volume":"84","author":"M Takahashi","year":"1987","unstructured":"Takahashi, M., Seagar, M. J., Jones, J. F., Reber, B. F. & Catterall, W. A. Subunit structure of dihydropyridine-sensitive calcium channels from skeletal muscle. Proc. Natl. Acad. Sci. USA 84, 5478\u20135482 (1987).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"959_CR6","doi-asserted-by":"publisher","first-page":"33840","DOI":"10.1074\/jbc.M105386200","volume":"276","author":"F Van Goor","year":"2001","unstructured":"Van Goor, F., Zivadinovic, D., Martinez-Fuentes, A. J. & Stojilkovic, S. S. Dependence of pituitary hormone secretion on the pattern of spontaneous voltage-gated calcium influx. Cell type-specific action potential secretion coupling. J. Biol. Chem. 276, 33840\u201333846 (2001).","journal-title":"J. Biol. Chem."},{"key":"959_CR7","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1146\/annurev.bi.63.070194.004135","volume":"63","author":"BM Olivera","year":"1994","unstructured":"Olivera, B. M., Miljanich, G. P., Ramachandran, J. & Adams, M. E. Calcium channel diversity and neurotransmitter release: the omega-conotoxins and omega-agatoxins. Annu. Rev. Biochem. 63, 823\u2013867 (1994).","journal-title":"Annu. Rev. Biochem."},{"key":"959_CR8","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1146\/annurev.neuro.31.060407.125631","volume":"31","author":"SW Flavell","year":"2008","unstructured":"Flavell, S. W. & Greenberg, M. E. Signaling mechanisms linking neuronal activity to gene expression and plasticity of the nervous system. Annu. Rev. Neurosci. 31, 563\u2013590 (2008).","journal-title":"Annu. Rev. Neurosci."},{"key":"959_CR9","doi-asserted-by":"publisher","first-page":"863","DOI":"10.1126\/science.aad3647","volume":"351","author":"B Li","year":"2016","unstructured":"Li, B., Tadross, M. R. & Tsien, R. W. Sequential ionic and conformational signaling by calcium channels drives neuronal gene expression. Science 351, 863\u2013867 (2016).","journal-title":"Science"},{"key":"959_CR10","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1085\/jgp.201311153","volume":"143","author":"M Ben-Johny","year":"2014","unstructured":"Ben-Johny, M. & Yue, D. T. Calmodulin regulation (calmodulation) of voltage-gated calcium channels. J. Gen. Physiol. 143, 679\u2013692 (2014).","journal-title":"J. Gen. Physiol."},{"key":"959_CR11","doi-asserted-by":"publisher","first-page":"re15","DOI":"10.1126\/stke.3152005re15","volume":"2005","author":"DB Halling","year":"2005","unstructured":"Halling, D. B., Aracena-Parks, P. & Hamilton, S. L. Regulation of voltage-gated Ca2+ channels by calmodulin. Sci. STKE 2005, re15 (2005).","journal-title":"Sci. STKE"},{"key":"959_CR12","doi-asserted-by":"publisher","first-page":"1108","DOI":"10.1038\/nsmb1027","volume":"12","author":"F Van Petegem","year":"2005","unstructured":"Van Petegem, F., Chatelain, F. C. & Minor, D. L. Jr Insights into voltage-gated calcium channel regulation from the structure of the CaV1.2 IQ domain-Ca2+\/calmodulin complex. Nat. Struct. Mol. Biol. 12, 1108\u20131115 (2005).","journal-title":"Nat. Struct. Mol. Biol."},{"key":"959_CR13","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1016\/j.neuron.2010.07.001","volume":"67","author":"BC Suh","year":"2010","unstructured":"Suh, B. C., Leal, K. & Hille, B. Modulation of high-voltage activated Ca(2+) channels by membrane phosphatidylinositol 4,5-bisphosphate. Neuron 67, 224\u2013238 (2010).","journal-title":"Neuron"},{"key":"959_CR14","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-35026-6","volume":"13","author":"X Yao","year":"2022","unstructured":"Yao, X. et al. Structures of the R-type human Ca(v)2.3 channel reveal conformational crosstalk of the intracellular segments. Nat. Commun. 13, 7358 (2022).","journal-title":"Nat. Commun."},{"key":"959_CR15","doi-asserted-by":"publisher","first-page":"5363","DOI":"10.1016\/j.cell.2023.10.007","volume":"186","author":"S Gao","year":"2023","unstructured":"Gao, S. et al. Structural basis for human Ca(v)1.2 inhibition by multiple drugs and the neurotoxin calciseptine. Cell 186, 5363\u20135374.e16 (2023).","journal-title":"Cell"},{"key":"959_CR16","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1124\/pr.55.4.3","volume":"55","author":"AC Dolphin","year":"2003","unstructured":"Dolphin, A. C. G protein modulation of voltage-gated calcium channels. Pharmacol. Rev. 55, 607\u2013627 (2003).","journal-title":"Pharmacol. Rev."},{"issue":"1","key":"959_CR17","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1111\/j.1469-7793.1998.003bx.x","volume":"506","author":"AC Dolphin","year":"1998","unstructured":"Dolphin, A. C. Mechanisms of modulation of voltage-dependent calcium channels by G proteins. J. Physiol. 506(1), 3\u201311 (1998).","journal-title":"J. Physiol."},{"key":"959_CR18","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1038\/nature01772","volume":"424","author":"JT Wolfe","year":"2003","unstructured":"Wolfe, J. T., Wang, H., Howard, J., Garrison, J. C. & Barrett, P. Q. T-type calcium channel regulation by specific G-protein betagamma subunits. Nature 424, 209\u2013213 (2003).","journal-title":"Nature"},{"key":"959_CR19","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1016\/j.toxicon.2006.09.022","volume":"49","author":"WA Catterall","year":"2007","unstructured":"Catterall, W. A. et al. Voltage-gated ion channels and gating modifier toxins. Toxicon 49, 124\u2013141 (2007).","journal-title":"Toxicon"},{"key":"959_CR20","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1146\/annurev-pharmtox-010818-021757","volume":"60","author":"WA Catterall","year":"2020","unstructured":"Catterall, W. A., Lenaeus, M. J. & Gamal El-Din, T. M. Structure and pharmacology of voltage-gated sodium and calcium channels. Annu. Rev. Pharmacol. Toxicol. 60, 133\u2013154 (2020).","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"959_CR21","doi-asserted-by":"publisher","first-page":"1495","DOI":"10.1016\/j.cell.2019.04.043","volume":"177","author":"Y Zhao","year":"2019","unstructured":"Zhao, Y. et al. Molecular basis for ligand modulation of a mammalian voltage-gated Ca(2+) channel. Cell 177, 1495\u20131506.e12 (2019).","journal-title":"Cell"},{"key":"959_CR22","doi-asserted-by":"publisher","first-page":"3131","DOI":"10.1002\/anie.202011793","volume":"60","author":"S Gao","year":"2021","unstructured":"Gao, S. & Yan, N. Structural basis of the modulation of the voltage-gated calcium ion channel Ca(v) 1.1 by dihydropyridine compounds*. Angew Chem. Int. Ed. Engl. 60, 3131\u20133137 (2021).","journal-title":"Angew Chem. Int. Ed. Engl."},{"key":"959_CR23","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1038\/s41586-021-03699-6","volume":"596","author":"S Gao","year":"2021","unstructured":"Gao, S., Yao, X. & Yan, N. Structure of human Ca(v)2.2 channel blocked by the painkiller ziconotide. Nature 596, 143\u2013147 (2021).","journal-title":"Nature"},{"key":"959_CR24","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.pneurobio.2014.12.003","volume":"129","author":"F Neumaier","year":"2015","unstructured":"Neumaier, F., Dibue-Adjei, M., Hescheler, J. & Schneider, T. Voltage-gated calcium channels: Determinants of channel function and modulation by inorganic cations. Prog. Neurobiol. 129, 1\u201336 (2015).","journal-title":"Prog. Neurobiol."},{"key":"959_CR25","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1038\/316440a0","volume":"316","author":"MC Nowycky","year":"1985","unstructured":"Nowycky, M. C., Fox, A. P. & Tsien, R. W. Three types of neuronal calcium channel with different calcium agonist sensitivity. Nature 316, 440\u2013443 (1985).","journal-title":"Nature"},{"key":"959_CR26","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1016\/S0896-6273(00)81057-0","volume":"25","author":"EA Ertel","year":"2000","unstructured":"Ertel, E. A. et al. Nomenclature of voltage-gated calcium channels. Neuron 25, 533\u2013535 (2000).","journal-title":"Neuron"},{"key":"959_CR27","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1124\/pr.57.4.5","volume":"57","author":"WA Catterall","year":"2005","unstructured":"Catterall, W. A., Perez-Reyes, E., Snutch, T. P. & Striessnig, J. International union of pharmacology. XLVIII. Nomenclature and structure-function relationships of voltage-gated calcium channels. Pharmacol. Rev. 57, 411\u2013425 (2005).","journal-title":"Pharmacol. Rev."},{"key":"959_CR28","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1023\/B:JOBB.0000008022.50702.1a","volume":"35","author":"CJ Doering","year":"2003","unstructured":"Doering, C. J. & Zamponi, G. W. Molecular pharmacology of high voltage-activated calcium channels. J. Bioenerg. Biomembr. 35, 491\u2013505 (2003).","journal-title":"J. Bioenerg. Biomembr."},{"key":"959_CR29","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/j.ceca.2006.04.012","volume":"40","author":"E Perez-Reyes","year":"2006","unstructured":"Perez-Reyes, E. Molecular characterization of T-type calcium channels. Cell Calcium 40, 89\u201396 (2006).","journal-title":"Cell Calcium"},{"key":"959_CR30","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1016\/S0959-4388(03)00066-7","volume":"13","author":"J Arikkath","year":"2003","unstructured":"Arikkath, J. & Campbell, K. P. Auxiliary subunits: essential components of the voltage-gated calcium channel complex. Curr. Opin. Neurobiol. 13, 298\u2013307 (2003).","journal-title":"Curr. Opin. Neurobiol."},{"key":"959_CR31","doi-asserted-by":"publisher","first-page":"879","DOI":"10.1016\/S0028-3908(97)00086-5","volume":"36","author":"AD Randall","year":"1997","unstructured":"Randall, A. D. & Tsien, R. W. Contrasting biophysical and pharmacological properties of T-type and R-type calcium channels. Neuropharmacology 36, 879\u2013893 (1997).","journal-title":"Neuropharmacology"},{"key":"959_CR32","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1152\/physrev.00018.2002","volume":"83","author":"E Perez-Reyes","year":"2003","unstructured":"Perez-Reyes, E. Molecular physiology of low-voltage-activated t-type calcium channels. Physiol. Rev. 83, 117\u2013161 (2003).","journal-title":"Physiol. Rev."},{"key":"959_CR33","doi-asserted-by":"publisher","first-page":"1895","DOI":"10.1523\/JNEUROSCI.19-06-01895.1999","volume":"19","author":"EM Talley","year":"1999","unstructured":"Talley, E. M. et al. Differential distribution of three members of a gene family encoding low voltage-activated (T-type) calcium channels. J. Neurosci. 19, 1895\u20131911 (1999).","journal-title":"J. Neurosci."},{"key":"959_CR34","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1016\/j.celrep.2014.12.042","volume":"10","author":"A Francois","year":"2015","unstructured":"Francois, A. et al. The low-threshold calcium channel Cav3.2 determines low-threshold mechanoreceptor function. Cell Rep. 10, 370\u2013382 (2015).","journal-title":"Cell Rep."},{"key":"959_CR35","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1038\/sj.emboj.7600515","volume":"24","author":"E Bourinet","year":"2005","unstructured":"Bourinet, E. et al. Silencing of the Cav3.2 T-type calcium channel gene in sensory neurons demonstrates its major role in nociception. EMBO J. 24, 315\u2013324 (2005).","journal-title":"EMBO J."},{"key":"959_CR36","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/j.trsl.2021.01.002","volume":"234","author":"S Cai","year":"2021","unstructured":"Cai, S., Gomez, K., Moutal, A. & Khanna, R. Targeting T-type\/CaV3.2 channels for chronic pain. Transl. Res. 234, 20\u201330 (2021).","journal-title":"Transl. Res."},{"key":"959_CR37","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1111\/j.1601-183X.2006.00268.x","volume":"6","author":"S Choi","year":"2007","unstructured":"Choi, S. et al. Attenuated pain responses in mice lacking Ca(V)3.2 T-type channels. Genes Brain Behav. 6, 425\u2013431 (2007).","journal-title":"Genes Brain Behav."},{"key":"959_CR38","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1002\/ana.20028","volume":"55","author":"SE Heron","year":"2004","unstructured":"Heron, S. E. et al. Genetic variation of CACNA1H in idiopathic generalized epilepsy. Ann. Neurol. 55, 595\u2013596 (2004).","journal-title":"Ann. Neurol."},{"key":"959_CR39","doi-asserted-by":"publisher","first-page":"9681","DOI":"10.1074\/jbc.C400006200","volume":"279","author":"H Khosravani","year":"2004","unstructured":"Khosravani, H. et al. Gating effects of mutations in the Cav3.2 T-type calcium channel associated with childhood absence epilepsy. J. Biol. Chem. 279, 9681\u20139684 (2004).","journal-title":"J. Biol. Chem."},{"key":"959_CR40","doi-asserted-by":"publisher","first-page":"2375","DOI":"10.1111\/bph.13906","volume":"175","author":"TP Snutch","year":"2018","unstructured":"Snutch, T. P. & Zamponi, G. W. Recent advances in the development of T-type calcium channel blockers for pain intervention. Br. J. Pharmacol. 175, 2375\u20132383 (2018).","journal-title":"Br. J. Pharmacol."},{"key":"959_CR41","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1016\/j.eplepsyres.2008.11.010","volume":"83","author":"N Matar","year":"2009","unstructured":"Matar, N. et al. Zonisamide block of cloned human T-type voltage-gated calcium channels. Epilepsy Res. 83, 224\u2013234 (2009).","journal-title":"Epilepsy Res."},{"key":"959_CR42","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1124\/jpet.108.145672","volume":"328","author":"E Perez-Reyes","year":"2009","unstructured":"Perez-Reyes, E., Van Deusen, A. L. & Vitko, I. Molecular pharmacology of human Cav3.2 T-type Ca2+ channels: block by antihypertensives, antiarrhythmics, and their analogs. J. Pharmacol. Exp. Ther. 328, 621\u2013627 (2009).","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"959_CR43","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1016\/j.pain.2012.10.023","volume":"154","author":"A Francois","year":"2013","unstructured":"Francois, A. et al. State-dependent properties of a new T-type calcium channel blocker enhance Ca(V)3.2 selectivity and support analgesic effects. Pain 154, 283\u2013293 (2013).","journal-title":"Pain"},{"key":"959_CR44","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1038\/s41586-019-1801-3","volume":"576","author":"Y Zhao","year":"2019","unstructured":"Zhao, Y. et al. Cryo-EM structures of apo and antagonist-bound human Ca(v)3.1. Nature 576, 492\u2013497 (2019).","journal-title":"Nature"},{"key":"959_CR45","doi-asserted-by":"publisher","first-page":"730","DOI":"10.1021\/cn200090z","volume":"2","author":"Z Xiang","year":"2011","unstructured":"Xiang, Z. et al. The discovery and characterization of ML218: A novel, centrally active T-type calcium channel inhibitor with robust effects in STN neurons and in a rodent model of Parkinson\u2019s disease. ACS Chem. Neurosci. 2, 730\u2013742 (2011).","journal-title":"ACS Chem. Neurosci."},{"key":"959_CR46","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1080\/13543776.2018.1541982","volume":"28","author":"G Nam","year":"2018","unstructured":"Nam, G. T-type calcium channel blockers: a patent review (2012-2018). Expert Opin. Ther. Pat. 28, 883\u2013901 (2018).","journal-title":"Expert Opin. Ther. Pat."},{"key":"959_CR47","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-29728-0","volume":"13","author":"L He","year":"2022","unstructured":"He, L. et al. Structure, gating, and pharmacology of human Ca(V)3.3 channel. Nat. Commun. 13, 2084 (2022).","journal-title":"Nat. Commun."},{"key":"959_CR48","doi-asserted-by":"publisher","first-page":"16168","DOI":"10.1074\/jbc.M114.634261","volume":"290","author":"A Monteil","year":"2015","unstructured":"Monteil, A. et al. Inhibition of Cav3.2 T-type calcium channels by its intracellular I-II loop. J. Biol. Chem. 290, 16168\u201316176 (2015).","journal-title":"J. Biol. Chem."},{"key":"959_CR49","doi-asserted-by":"publisher","first-page":"3765","DOI":"10.1016\/j.febslet.2008.10.013","volume":"582","author":"A Shcheglovitov","year":"2008","unstructured":"Shcheglovitov, A. et al. Alternative splicing within the I-II loop controls surface expression of T-type Ca(v)3.1 calcium channels. FEBS Lett. 582, 3765\u20133770 (2008).","journal-title":"FEBS Lett."},{"key":"959_CR50","doi-asserted-by":"publisher","first-page":"1159","DOI":"10.1007\/s00424-013-1259-3","volume":"465","author":"N Weiss","year":"2013","unstructured":"Weiss, N., Black, S. A., Bladen, C., Chen, L. & Zamponi, G. W. Surface expression and function of Cav3.2 T-type calcium channels are controlled by asparagine-linked glycosylation. Pflugers Arch. 465, 1159\u20131170 (2013).","journal-title":"Pflugers Arch."},{"key":"959_CR51","doi-asserted-by":"publisher","DOI":"10.1186\/s13041-020-00697-z","volume":"13","author":"V Ficelova","year":"2020","unstructured":"Ficelova, V. et al. Functional identification of potential non-canonical N-glycosylation sites within Ca(v)3.2 T-type calcium channels. Mol. Brain 13, 149 (2020).","journal-title":"Mol. Brain"},{"key":"959_CR52","doi-asserted-by":"publisher","first-page":"3828","DOI":"10.2337\/db13-0813","volume":"62","author":"P Orestes","year":"2013","unstructured":"Orestes, P. et al. Reversal of neuropathic pain in diabetes by targeting glycosylation of Ca(V)3.2 T-type calcium channels. Diabetes 62, 3828\u20133838 (2013).","journal-title":"Diabetes"},{"key":"959_CR53","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-38942-3","volume":"14","author":"Q Wu","year":"2023","unstructured":"Wu, Q. et al. Structural mapping of Na(v)1.7 antagonists. Nat. Commun. 14, 3224 (2023).","journal-title":"Nat. Commun."},{"key":"959_CR54","doi-asserted-by":"publisher","first-page":"2287832","DOI":"10.1080\/19336950.2023.2287832","volume":"18","author":"Z Li","year":"2024","unstructured":"Li, Z., Wu, Q. & Yan, N. A structural atlas of druggable sites on Na(v) channels. Channels 18, 2287832 (2024).","journal-title":"Channels"},{"key":"959_CR55","doi-asserted-by":"publisher","first-page":"13341","DOI":"10.1523\/JNEUROSCI.1421-08.2008","volume":"28","author":"AJ Becker","year":"2008","unstructured":"Becker, A. J. et al. Transcriptional upregulation of Cav3.2 mediates epileptogenesis in the pilocarpine model of epilepsy. J. Neurosci. 28, 13341\u201313353 (2008).","journal-title":"J. Neurosci."},{"key":"959_CR56","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1523\/JNEUROSCI.1817-06.2007","volume":"27","author":"I Vitko","year":"2007","unstructured":"Vitko, I. et al. The I-II loop controls plasma membrane expression and gating of Ca(v)3.2 T-type Ca2+ channels: a paradigm for childhood absence epilepsy mutations. J. Neurosci. 27, 322\u2013330 (2007).","journal-title":"J. Neurosci."},{"key":"959_CR57","doi-asserted-by":"publisher","first-page":"560","DOI":"10.1002\/ana.21169","volume":"62","author":"SE Heron","year":"2007","unstructured":"Heron, S. E. et al. Extended spectrum of idiopathic generalized epilepsies associated with CACNA1H functional variants. Ann. Neurol. 62, 560\u2013568 (2007).","journal-title":"Ann. Neurol."},{"key":"959_CR58","doi-asserted-by":"publisher","first-page":"22085","DOI":"10.1074\/jbc.M603316200","volume":"281","author":"I Splawski","year":"2006","unstructured":"Splawski, I. et al. CACNA1H mutations in autism spectrum disorders. J. Biol. Chem. 281, 22085\u201322091 (2006).","journal-title":"J. Biol. Chem."},{"key":"959_CR59","doi-asserted-by":"publisher","first-page":"466","DOI":"10.1080\/19336950.2016.1204497","volume":"10","author":"Y Rzhepetskyy","year":"2016","unstructured":"Rzhepetskyy, Y., Lazniewska, J., Blesneac, I., Pamphlett, R. & Weiss, N. CACNA1H missense mutations associated with amyotrophic lateral sclerosis alter Cav3.2 T-type calcium channel activity and reticular thalamic neuron firing. Channels 10, 466\u2013477 (2016).","journal-title":"Channels"},{"key":"959_CR60","doi-asserted-by":"publisher","DOI":"10.1186\/s13041-020-00577-6","volume":"13","author":"RN Stringer","year":"2020","unstructured":"Stringer, R. N. et al. A rare CACNA1H variant associated with amyotrophic lateral sclerosis causes complete loss of Ca(v)3.2 T-type channel activity. Mol. Brain 13, 33 (2020).","journal-title":"Mol. Brain"},{"key":"959_CR61","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.110735","volume":"39","author":"G Huang","year":"2022","unstructured":"Huang, G. et al. High-resolution structures of human Na(v)1.7 reveal gating modulation through \u03b1-\u03c0 helical transition of S6(IV). Cell Rep. 39, 110735 (2022).","journal-title":"Cell Rep."},{"key":"959_CR62","doi-asserted-by":"publisher","first-page":"4801","DOI":"10.1016\/j.cell.2022.10.024","volume":"185","author":"X Yao","year":"2022","unstructured":"Yao, X. et al. Structural basis for the severe adverse interaction of sofosbuvir and amiodarone on L-type Ca(v) channels. Cell 185, 4801\u20134810.e13 (2022).","journal-title":"Cell"},{"key":"959_CR63","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1038\/nmeth.4169","volume":"14","author":"A Punjani","year":"2017","unstructured":"Punjani, A., Rubinstein, J. L., Fleet, D. J. & Brubaker, M. A. cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination. Nat. Methods 14, 290\u2013296 (2017).","journal-title":"Nat. Methods"},{"key":"959_CR64","doi-asserted-by":"publisher","unstructured":"Jamali, K. et al. Automated model building and protein identification in cryo-EM maps. Nature https:\/\/doi.org\/10.1038\/s41586-024-07215-4 (2024).","DOI":"10.1038\/s41586-024-07215-4"},{"key":"959_CR65","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1107\/S0907444910007493","volume":"66","author":"P Emsley","year":"2010","unstructured":"Emsley, P., Lohkamp, B., Scott, W. G. & Cowtan, K. Features and development of Coot. Acta Crystallogr. D Biol. Crystallogr. 66, 486\u2013501 (2010).","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"959_CR66","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1107\/S2059798319011471","volume":"75","author":"D Liebschner","year":"2019","unstructured":"Liebschner, D. et al. Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix. Acta Crystallogr. D Struct. Biol. 75, 861\u2013877 (2019).","journal-title":"Acta Crystallogr. D Struct. Biol."},{"key":"959_CR67","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1107\/S2059798318002425","volume":"74","author":"TI Croll","year":"2018","unstructured":"Croll, T. I. ISOLDE: a physically realistic environment for model building into low-resolution electron-density maps. Acta Crystallogr. D Struct. Biol. 74, 519\u2013530 (2018).","journal-title":"Acta Crystallogr. D Struct. Biol."},{"key":"959_CR68","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1007\/s10822-013-9644-8","volume":"27","author":"GM Sastry","year":"2013","unstructured":"Sastry, G. M., Adzhigirey, M., Day, T., Annabhimoju, R. & Sherman, W. Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J. Comput. Aided Mol. Des. 27, 221\u2013234 (2013).","journal-title":"J. Comput. Aided Mol. Des."},{"key":"959_CR69","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1021\/acs.jctc.5b00864","volume":"12","author":"E Harder","year":"2016","unstructured":"Harder, E. et al. OPLS3: a force field providing broad coverage of drug-like small molecules and proteins. J. Chem. Theory Comput. 12, 281\u2013296 (2016).","journal-title":"J. Chem. Theory Comput."},{"key":"959_CR70","doi-asserted-by":"publisher","first-page":"354","DOI":"10.1016\/S0263-7855(97)00009-X","volume":"14","author":"OS Smart","year":"1996","unstructured":"Smart, O. S., Neduvelil, J. G., Wang, X., Wallace, B. A. & Sansom, M. S. HOLE: a program for the analysis of the pore dimensions of ion channel structural models. J. Mol. Graph 14, 354\u2013360 (1996).","journal-title":"J. Mol. Graph"}],"container-title":["Cell Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41422-024-00959-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41422-024-00959-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41422-024-00959-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,31]],"date-time":"2024-05-31T08:05:10Z","timestamp":1717142710000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41422-024-00959-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,11]]},"references-count":70,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2024,6]]}},"alternative-id":["959"],"URL":"https:\/\/doi.org\/10.1038\/s41422-024-00959-8","relation":{},"ISSN":["1748-7838"],"issn-type":[{"value":"1748-7838","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,11]]},"assertion":[{"value":"21 December 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 April 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 April 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}