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The 2.1- and 2.2-\u212b crystal\n structures reported here for 4-phenylimidazole- and fluconazole-bound\n CYP51 from\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    (MTCYP51) are the\n first structures of an authentic P450 drug target. MTCYP51 exhibits the\n P450 fold with the exception of two striking differences\u2014a bent I\n helix and an open conformation of BC loop\u2014that define an active\n site-access channel running along the heme plane perpendicular to the\n direction observed for the substrate entry in P450BM3. Although a\n channel analogous to that in P450BM3 is evident also in MTCYP51, it is\n not open at the surface. The presence of two different channels, with\n one being open to the surface, suggests the possibility of\n conformationally regulated substrate-in\/product-out openings in\n CYP51. Mapping mutations identified in\n                    <jats:italic>Candida albicans<\/jats:italic>\n                    azole-resistant isolates indicates that azole resistance in fungi\n develops in protein regions involved in orchestrating passage of CYP51\n through different conformational stages along the catalytic cycle\n rather than in residues directly contacting fluconazole. These new\n structures provide a basis for rational design of new, more efficacious\n antifungal agents as well as insight into the molecular mechanism of\n P450 catalysis.\n                  <\/jats:p>","DOI":"10.1073\/pnas.061562898","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:36:44Z","timestamp":1027679804000},"page":"3068-3073","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":479,"title":["Crystal structure of cytochrome P450 14\u03b1-sterol demethylase (CYP51) from\n                    <i>Mycobacterium tuberculosis<\/i>\n                    in complex with azole inhibitors"],"prefix":"10.1073","volume":"98","author":[{"given":"Larissa M.","family":"Podust","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Vanderbilt University School of\r Medicine, Nashville, TN 37232-0146; and Departments of\r Molecular Biology and Biochemistry, Physiology, and Biophysics, and 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