{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T19:29:22Z","timestamp":1786994962286,"version":"build-2736575974"},"reference-count":41,"publisher":"American Chemical Society (ACS)","issue":"9","license":[{"start":{"date-parts":[[2020,9,3]],"date-time":"2020-09-03T00:00:00Z","timestamp":1599091200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2020,9,3]],"date-time":"2020-09-03T00:00:00Z","timestamp":1599091200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2020,9,3]],"date-time":"2020-09-03T00:00:00Z","timestamp":1599091200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["P50NS047085"],"award-info":[{"award-number":["P50NS047085"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["U01NS080409"],"award-info":[{"award-number":["U01NS080409"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000864","name":"Michael J. Fox Foundation for Parkinson's Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000864","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007457","name":"JPB Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007457","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,9,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Ca2+ channels with a CaV1.3 pore-forming \u03b11 subunit have been implicated in both neurodegenerative and neuropsychiatric disorders, motivating the development of selective and potent inhibitors of CaV1.3 versus CaV1.2 channels, the calcium channels implicated in hypertensive disorders. We have previously identified pyrimidine-2,4,6-triones (PYTs) that preferentially inhibit CaV1.3 channels, but the structural determinants of their interaction with the channel have not been identified, impeding their development into drugs. By a combination of biochemical, computational, and molecular biological approaches, it was found that PYTs bind to the dihydropyridine (DHP) binding pocket of the CaV1.3 subunit, establishing them as negative allosteric modulators of channel gating. Site-directed mutagenesis, based on homology models of CaV1.3 and CaV1.2 channels, revealed that a single amino acid residue within the DHP binding pocket (M1078) is responsible for the selectivity of PYTs for CaV1.3 over CaV1.2. In addition to providing direction for chemical optimization, these results suggest that, like dihydropyridines, PYTs have pharmacological features that could make them of broad clinical utility.<\/jats:p>","DOI":"10.1021\/acschembio.0c00577","type":"journal-article","created":{"date-parts":[[2020,9,3]],"date-time":"2020-09-03T12:54:40Z","timestamp":1599137680000},"page":"2539-2550","source":"Crossref","is-referenced-by-count":17,"title":["A Single Amino Acid Determines the Selectivity and\nEfficacy of Selective Negative Allosteric Modulators of CaV1.3 L\u2011Type Calcium Channels"],"prefix":"10.1021","volume":"15","author":[{"given":"Garry","family":"Cooper","sequence":"first","affiliation":[{"name":"Northwestern University , , , ,","place":["Evanston, Illinois, United States, 60208-3113"]},{"name":"Northwestern University , , , ,","place":["Chicago, Illinois, United States, 60611"]},{"name":"Northwestern University , , , ,","place":["Evanston, Illinois, United States, 60208"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7016-2417","authenticated-orcid":true,"given":"Soosung","family":"Kang","sequence":"additional","affiliation":[{"name":"Northwestern University , , , ,","place":["Evanston, Illinois, United States, 60208-3113"]},{"name":"Northwestern University , , , ,","place":["Evanston, Illinois, United States, 60208"]},{"name":"Ewha Womans University , , ,","place":["Seoul, Korea, 03760"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamara","family":"Perez-Rosello","sequence":"additional","affiliation":[{"name":"Northwestern University , , , ,","place":["Chicago, Illinois, United States, 60611"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaime N.","family":"Guzman","sequence":"additional","affiliation":[{"name":"Northwestern University , , , ,","place":["Chicago, Illinois, United States, 60611"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Galtieri","sequence":"additional","affiliation":[{"name":"Northwestern University , , , ,","place":["Chicago, Illinois, United States, 60611"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhong","family":"Xie","sequence":"additional","affiliation":[{"name":"Northwestern University , , , ,","place":["Chicago, Illinois, United States, 60611"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jyothisri","family":"Kondapalli","sequence":"additional","affiliation":[{"name":"Northwestern University , , , ,","place":["Chicago, Illinois, United States, 60611"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack","family":"Mordell","sequence":"additional","affiliation":[{"name":"Northwestern University , , , ,","place":["Chicago, Illinois, United States, 60611"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9034-1084","authenticated-orcid":true,"given":"Richard B.","family":"Silverman","sequence":"additional","affiliation":[{"name":"Northwestern University , , , ,","place":["Evanston, Illinois, United States, 60208-3113"]},{"name":"Northwestern University , , , ,","place":["Evanston, Illinois, United States, 60208"]},{"name":"Northwestern University , , , ,","place":["Chicago, Illinois, United States, 60611"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. James","family":"Surmeier","sequence":"additional","affiliation":[{"name":"Northwestern University , , , ,","place":["Chicago, Illinois, United States, 60611"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2020,9,3]]},"reference":[{"issue":"8","key":"2026081714191094200_cit1","doi-asserted-by":"publisher","first-page":"a003947","DOI":"10.1101\/cshperspect.a003947","article-title":"Voltage-gated calcium channels","volume":"3","author":"Catterall","year":"2011","journal-title":"Cold Spring Harbor Perspect. Biol."},{"issue":"4","key":"2026081714191094200_cit2","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1124\/pr.55.4.8","article-title":"International\nUnion of Pharmacology. XL. Compendium of voltage-gated ion channels:\ncalcium channels","volume":"55","author":"Catterall","year":"2003","journal-title":"Pharmacol. 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