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DHP compounds exhibit chirality\u2010specific antagonistic or agonistic effects. The structure of rabbit Ca<jats:sub>v<\/jats:sub>1.1 bound to an achiral drug nifedipine reveals the general binding mode for DHP drugs, but the molecular basis for chiral specificity remained elusive. Herein, we report five cryo\u2010EM structures of nanodisc\u2010embedded Ca<jats:sub>v<\/jats:sub>1.1 in the presence of the bestselling drug amlodipine, a DHP antagonist (<jats:italic>R<\/jats:italic>)\u2010(+)\u2010Bay K8644, and a titration of its agonistic enantiomer (<jats:italic>S<\/jats:italic>)\u2010(\u2212)\u2010Bay K8644 at resolutions of 2.9\u20133.4\u2005\u00c5. The amlodipine\u2010bound structure reveals the molecular basis for the high efficacy of the drug. All structures with the addition of the Bay K8644 enantiomers exhibit similar inactivated conformations, suggesting that (<jats:italic>S<\/jats:italic>)\u2010(\u2212)\u2010Bay K8644, when acting as an agonist, is insufficient to lock the activated state of the channel for a prolonged duration.<\/jats:p>","DOI":"10.1002\/anie.202011793","type":"journal-article","created":{"date-parts":[[2020,10,30]],"date-time":"2020-10-30T19:25:52Z","timestamp":1604085952000},"page":"3131-3137","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":78,"title":["Structural Basis of the Modulation of the Voltage\u2010Gated Calcium Ion Channel Ca<sub>v<\/sub>1.1 by Dihydropyridine Compounds**"],"prefix":"10.1002","volume":"60","author":[{"given":"Shuai","family":"Gao","sequence":"first","affiliation":[{"name":"Department of Molecular Biology Princeton University  Princeton NJ 08544 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4829-7416","authenticated-orcid":false,"given":"Nieng","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology Princeton University  Princeton NJ 08544 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,12,10]]},"reference":[{"key":"e_1_2_6_1_1","unstructured":"\u00a0"},{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a003947"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.11.028"},{"key":"e_1_2_6_4_1","unstructured":"\u00a0"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)81057-0"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/316440a0"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.114.009654"},{"key":"e_1_2_6_8_1","unstructured":"\u00a0"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd.2015.5"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.2165\/00003495-198530030-00002"},{"key":"e_1_2_6_11_1","unstructured":"\u00a0"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0706442"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.37.1.361"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.199115591"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.1002\/ange.19911031206"},{"key":"e_1_2_6_15_1","unstructured":"\u00a0"},{"key":"e_1_2_6_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(85)90631-4"},{"key":"e_1_2_6_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/303535a0"},{"key":"e_1_2_6_18_1","unstructured":"\u00a0"},{"key":"e_1_2_6_19_2","doi-asserted-by":"publisher","DOI":"10.1097\/00005344-198503000-00025"},{"key":"e_1_2_6_20_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00384362"},{"key":"e_1_2_6_21_1","unstructured":"\u00a0"},{"key":"e_1_2_6_22_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00181955"},{"key":"e_1_2_6_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2012.123"},{"key":"e_1_2_6_24_1","unstructured":"\u00a0"},{"key":"e_1_2_6_25_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aad2395"},{"key":"e_1_2_6_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature19321"},{"key":"e_1_2_6_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.04.043"},{"key":"e_1_2_6_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1801-3"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1922903117"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.10.5293"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.93.6.1109"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm00159a022"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1097\/00005344-199104000-00010"},{"key":"e_1_2_6_34_1","first-page":"634","volume":"36","author":"Mason R. 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