{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T05:09:35Z","timestamp":1788671375107,"version":"build-2803163510"},"reference-count":33,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2019,8,30]],"date-time":"2019-08-30T00:00:00Z","timestamp":1567123200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["ES025767"],"award-info":[{"award-number":["ES025767"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Human cytochrome P450 3A4 (CYP3A4) is the most important drug-metabolizing enzyme. Some drugs and natural compounds can act as suicide (mechanism-based) inactivators of CYP3A4, leading to unanticipated drug-drug interactions, toxicity and therapeutic failures. Despite significant clinical and toxicological implications, the mechanism-based inactivation remains incompletely understood. This study provides the first direct insights into the interaction of CYP3A4 with three suicide substrates: mibefradil, an antihypertensive drug quickly withdrawn from the market; a semi-synthetic antibiotic azamulin; and a natural furanocoumarin, 6\u2032,7\u2032-dihydroxybergamottin. Novel structural findings help better understand the suicide substrate binding and inhibitory mechanism, and can be used to improve the predictability of the binding ability, metabolic sites and inhibitory\/inactivation potential of newly developed drugs and other chemicals relevant to public health.<\/jats:p>","DOI":"10.3390\/ijms20174245","type":"journal-article","created":{"date-parts":[[2019,8,30]],"date-time":"2019-08-30T10:31:17Z","timestamp":1567161077000},"page":"4245","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Structural Insights into the Interaction of Cytochrome P450 3A4 with Suicide Substrates: Mibefradil, Azamulin and 6\u2032,7\u2032-Dihydroxybergamottin"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4498-6057","authenticated-orcid":false,"given":"Irina F.","family":"Sevrioukova","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697-3900, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,8,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1146\/annurev.pharmtox.39.1.1","article-title":"Cytochrome P-450 3A4: Regulation and role in drug metabolism","volume":"39","author":"Guengerich","year":"1999","journal-title":"Annu. 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