{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T16:55:58Z","timestamp":1781110558990,"version":"3.54.1"},"reference-count":57,"publisher":"National Academy of Sciences","issue":"24","license":[{"start":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T00:00:00Z","timestamp":1749686400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100023885","name":"HHS | NIH | All of Us Research Program","doi-asserted-by":"publisher","award":["CA290129"],"award-info":[{"award-number":["CA290129"]}],"id":[{"id":"10.13039\/100023885","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100023885","name":"HHS | NIH | All of Us Research Program","doi-asserted-by":"publisher","award":["GM130389"],"award-info":[{"award-number":["GM130389"]}],"id":[{"id":"10.13039\/100023885","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":[[2025,6,17]]},"abstract":"<jats:p>\n                    Cushing\u2019s syndrome (CS) is an abnormal condition characterized by elevated cortisol levels, often resulting from genetic alterations in the\n                    <jats:italic toggle=\"yes\">PRKACA<\/jats:italic>\n                    gene, which encodes the catalytic subunit of cAMP-dependent protein kinase A (PKA-C). The most common CS mutation, L205R, lies at the P + 1 loop. Understanding how this mutation alters the internal allosteric network within PKA-C and changes nucleotide and substrate cooperativity is a major goal. Using molecular dynamics (MD) simulations and protein residue networks based on local spatial pattern (LSP) method, we compare crystal structures of wild-type PKA-C and L205R. Our findings indicate that L205R not only locally disrupts the P + 1 hydrophobic pocket, leading to the displacement of the P + 1-residue and altered substrate specificity, but also has long-range effects in the linker connecting the A helix to \u03b2 strand 1. The MD simulations and LSP analyses also reveal critical changes at the phosphoryl transfer site. Some of these changes are captured in the L205R crystal structure while others are not. With this strategy, we also show how the dynamics of local and distal allosteric networks are differentially influenced by backbone and side-chain dynamics.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2502898122","type":"journal-article","created":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T10:49:07Z","timestamp":1749725347000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":1,"title":["Local and distal changes in dynamics are caused by an L205R Cushing\u2019s syndrome mutant in PRKACA"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-7189-1042","authenticated-orcid":false,"given":"Anagha","family":"Kalle","sequence":"first","affiliation":[{"name":"Advanced Academic Program, Johns Hopkins University","place":["Washington"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of California","place":["San Diego, La Jolla"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caesar","family":"Tawfeeq","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of California, San Diego","place":["La Jolla"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1543-3795","authenticated-orcid":false,"given":"Alexandr P.","family":"Kornev","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of California","place":["San Diego, La Jolla"]},{"name":"LSP Consulting LLC","place":["Temecula"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2795-6964","authenticated-orcid":false,"given":"Gianluigi","family":"Veglia","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota","place":["Minneapolis"]},{"name":"Department of Chemistry, University of Minnesota","place":["Minneapolis"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5078-6775","authenticated-orcid":false,"given":"Rodrigo","family":"Maillard","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Georgetown University","place":["Washington"]},{"name":"Institute for Soft Matter Synthesis and Metrology, Georgetown University","place":["Washington"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7702-6108","authenticated-orcid":false,"given":"Susan S.","family":"Taylor","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of California","place":["San Diego, La Jolla"]},{"name":"Department of Chemistry and Biochemistry, University of California, San Diego","place":["La Jolla"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nisha Amarnath","family":"Jonniya","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of California","place":["San Diego, La Jolla"]},{"name":"Department of Biotechnology, National Institute of Technology","place":["Andhra Pradesh, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,6,12]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.3892\/ijmm.2017.3036"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2203"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb0502-e127"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2010.11.018"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.bi.59.070190.004543"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.cb.08.110192.002241"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(03)00452-6"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2002.tb04323.x"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2016.10.033"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1042\/BCJ20230183"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M805862200"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1002\/iub.2714"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1862342"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1862343"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2015.09.002"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2021.100746"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1002\/1873-3468.12562"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abo0696"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2018-00775"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444993000423"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1424206112"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0607656103"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0807988105"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2215420119"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1621154114"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature11271"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-08655-7"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2023.168395"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1002\/1873-3468.14610"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0610251104"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2021.167123"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.1600663"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb1132"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.91980.3"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1021\/cr000226k"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)32719-4"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms6939"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2300902120"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2017.05.011"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.95481.2"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.95334.4"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.20290"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jctc.5b00255"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.10262"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1021\/ct3000734"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00894-005-0028-4"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1063\/1.1808117"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1080\/00268978800101881"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1063\/1.448118"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1063\/1.464397"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/0021-9991(77)90098-5"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1749933"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1021\/ct9005745"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1021\/ct400341p"},{"key":"e_1_3_4_55_2","first-page":"1","article-title":"The igraph software package for complex network research","volume":"1695","author":"Csardi G.","year":"2006","unstructured":"G. Csardi, T. Nepusz, The igraph software package for complex network research. Int. J. Complex Syst. 1695, 1\u20139 (2006).","journal-title":"Int. J. Complex Syst."},{"key":"e_1_3_4_56_2","unstructured":"G. Cs\u00e1rdi igraph: Network Analysis and Visualization in R. R package version 2.1.4 (2025) 10.5281\/zenodo.7682609."},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0098679"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2502898122","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T10:49:52Z","timestamp":1749725392000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2502898122"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,12]]},"references-count":57,"journal-issue":{"issue":"24","published-print":{"date-parts":[[2025,6,17]]}},"alternative-id":["10.1073\/pnas.2502898122"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2502898122","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,12]]},"assertion":[{"value":"2025-02-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-05-07","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-12","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2502898122"}}