{"id":7555,"date":"2017-05-11T00:00:00","date_gmt":"2017-05-10T22:00:00","guid":{"rendered":"https:\/\/irb.usi.ch\/uncategorized\/new-paper-by-the-cavalli-lab-2\/"},"modified":"2017-05-11T00:00:00","modified_gmt":"2017-05-10T22:00:00","slug":"new-paper-by-the-cavalli-lab-2","status":"publish","type":"post","link":"https:\/\/irb.usi.ch\/it\/news\/new-paper-by-the-cavalli-lab-2\/","title":{"rendered":"New paper by the Cavalli Lab"},"content":{"rendered":"

on<\/span> May 11, 2017<\/span><\/p>\n

\"\"<\/p>\n

Cytochromes P450 (CYP450s), in particular, CYP19A1 and CYP17A1, are key clinical targets of breast and prostate anticancer therapies, critical players in drug metabolism, and their overexpression in tumors is associated with drug resistance. In these enzymes, ligand (substrates, drugs) metabolism occurs in deeply buried active sites accessible only via several grueling channels, whose exact biological role remains unclear. Gaining direct insights on the mechanism by which ligands travel in and out is becoming increasingly important given that channels are involved in the modulation of binding\/dissociation kinetics and the specificity of ligands toward a CYP450. This has profound implications for enzymatic efficiency and drug efficacy\/toxicity. Here, by applying free energy methods, for a cumulative simulation time of 20 \u03bcs, we provide detailed atomistic characterization and free energy profiles of the entry\/exit routes preferentially followed by a substrate (androstenedione) and a last-generation inhibitor (letrozole) to\/from the catalytic site of CYP19A1 (the human aromatase (HA) enzyme), a key clinical target against breast cancer, studied here as prototypical CYP450. Despite the remarkably different size\/shape\/hydrophobicity of the ligands, two channels appear accessible to their entrance, while only one exit route appears to be preferential. Our study shows that the preferential paths may be conserved among different CYP450s. Moreover, our results highlight that, at least in the case of HA, ligand channeling is associated with large enzyme structural rearrangements. A wise choice of the computational method and very long simulations are, thus, required to obtain fully converged quantitative free energy profiles, which might be used to design novel biocatalysts or next-generation cytochrome inhibitors with an in silico tuned K<\/em>m.<\/p>\n

Article<\/strong><\/p>\n

Single or Multiple Access Channels to the CYP450s Active Site? an Answer from Free Energy Simulations of the Human Aromatase Enzyme<\/a>.<\/p>\n

Magistrato, A., J. Sgrignani, R. Krause and A. Cavalli<\/p>\n

J Phys Chem Lett. 2017; In Press<\/em><\/p>\n","protected":false},"excerpt":{"rendered":"

on May 11, 2017 Cytochromes P450 (CYP450s), in particular, CYP19A1 and CYP17A1, are key clinical targets of breast and prostate anticancer therapies, critical players in drug metabolism, and their overexpression in tumors is associated with drug resistance. In these enzymes, ligand (substrates, drugs) metabolism occurs in deeply buried active sites accessible only via several grueling […]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":[],"categories":[16],"tags":[],"yoast_head":"\nNew paper by the Cavalli Lab - IRB USI<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/irb.usi.ch\/it\/news\/new-paper-by-the-cavalli-lab-2\/\" \/>\n<meta property=\"og:locale\" content=\"it_IT\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"New paper by the Cavalli Lab - IRB USI\" \/>\n<meta property=\"og:description\" content=\"on May 11, 2017 Cytochromes P450 (CYP450s), in particular, CYP19A1 and CYP17A1, are key clinical targets of breast and prostate anticancer therapies, critical players in drug metabolism, and their overexpression in tumors is associated with drug resistance. In these enzymes, ligand (substrates, drugs) metabolism occurs in deeply buried active sites accessible only via several grueling […]\" \/>\n<meta property=\"og:url\" content=\"https:\/\/irb.usi.ch\/it\/news\/new-paper-by-the-cavalli-lab-2\/\" \/>\n<meta property=\"og:site_name\" content=\"IRB USI\" \/>\n<meta property=\"article:published_time\" content=\"2017-05-10T22:00:00+00:00\" \/>\n<meta property=\"og:image\" content=\"https:\/\/irb.usi.ch\/images\/magistrato_cavalli_paper_may2017.jpg\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<meta name=\"twitter:label1\" content=\"Tempo di lettura stimato\">\n\t<meta name=\"twitter:data1\" content=\"2 minuti\">\n<script type=\"application\/ld+json\" class=\"yoast-schema-graph\">{\"@context\":\"https:\/\/schema.org\",\"@graph\":[{\"@type\":\"WebSite\",\"@id\":\"https:\/\/irb.usi.ch\/it\/#website\",\"url\":\"https:\/\/irb.usi.ch\/it\/\",\"name\":\"IRB USI\",\"description\":\"Institute for Research in Biomedicine\",\"potentialAction\":[{\"@type\":\"SearchAction\",\"target\":\"https:\/\/irb.usi.ch\/it\/?s={search_term_string}\",\"query-input\":\"required name=search_term_string\"}],\"inLanguage\":\"it-IT\"},{\"@type\":\"ImageObject\",\"@id\":\"https:\/\/irb.usi.ch\/it\/news\/new-paper-by-the-cavalli-lab-2\/#primaryimage\",\"inLanguage\":\"it-IT\",\"url\":\"\/images\/magistrato_cavalli_paper_may2017.jpg\"},{\"@type\":\"WebPage\",\"@id\":\"https:\/\/irb.usi.ch\/it\/news\/new-paper-by-the-cavalli-lab-2\/#webpage\",\"url\":\"https:\/\/irb.usi.ch\/it\/news\/new-paper-by-the-cavalli-lab-2\/\",\"name\":\"New paper by the Cavalli Lab - IRB USI\",\"isPartOf\":{\"@id\":\"https:\/\/irb.usi.ch\/it\/#website\"},\"primaryImageOfPage\":{\"@id\":\"https:\/\/irb.usi.ch\/it\/news\/new-paper-by-the-cavalli-lab-2\/#primaryimage\"},\"datePublished\":\"2017-05-10T22:00:00+00:00\",\"dateModified\":\"2017-05-10T22:00:00+00:00\",\"author\":{\"@id\":\"https:\/\/irb.usi.ch\/it\/#\/schema\/person\/c9b66c69925e1b0c558072acbadf4156\"},\"breadcrumb\":{\"@id\":\"https:\/\/irb.usi.ch\/it\/news\/new-paper-by-the-cavalli-lab-2\/#breadcrumb\"},\"inLanguage\":\"it-IT\",\"potentialAction\":[{\"@type\":\"ReadAction\",\"target\":[\"https:\/\/irb.usi.ch\/it\/news\/new-paper-by-the-cavalli-lab-2\/\"]}]},{\"@type\":\"BreadcrumbList\",\"@id\":\"https:\/\/irb.usi.ch\/it\/news\/new-paper-by-the-cavalli-lab-2\/#breadcrumb\",\"itemListElement\":[{\"@type\":\"ListItem\",\"position\":1,\"item\":{\"@type\":\"WebPage\",\"@id\":\"https:\/\/irb.usi.ch\/it\/\",\"url\":\"https:\/\/irb.usi.ch\/it\/\",\"name\":\"Home\"}},{\"@type\":\"ListItem\",\"position\":2,\"item\":{\"@type\":\"WebPage\",\"@id\":\"https:\/\/irb.usi.ch\/.\/news\/\",\"url\":\"https:\/\/irb.usi.ch\/.\/news\/\",\"name\":\"News\"}},{\"@type\":\"ListItem\",\"position\":3,\"item\":{\"@type\":\"WebPage\",\"@id\":\"https:\/\/irb.usi.ch\/it\/news\/new-paper-by-the-cavalli-lab-2\/\",\"url\":\"https:\/\/irb.usi.ch\/it\/news\/new-paper-by-the-cavalli-lab-2\/\",\"name\":\"New paper by the Cavalli Lab\"}}]},{\"@type\":\"Person\",\"@id\":\"https:\/\/irb.usi.ch\/it\/#\/schema\/person\/c9b66c69925e1b0c558072acbadf4156\",\"name\":\"AD_Dave\"}]}<\/script>\n<!-- \/ Yoast SEO plugin. -->","_links":{"self":[{"href":"https:\/\/irb.usi.ch\/it\/wp-json\/wp\/v2\/posts\/7555"}],"collection":[{"href":"https:\/\/irb.usi.ch\/it\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/irb.usi.ch\/it\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/irb.usi.ch\/it\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/irb.usi.ch\/it\/wp-json\/wp\/v2\/comments?post=7555"}],"version-history":[{"count":0,"href":"https:\/\/irb.usi.ch\/it\/wp-json\/wp\/v2\/posts\/7555\/revisions"}],"wp:attachment":[{"href":"https:\/\/irb.usi.ch\/it\/wp-json\/wp\/v2\/media?parent=7555"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/irb.usi.ch\/it\/wp-json\/wp\/v2\/categories?post=7555"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/irb.usi.ch\/it\/wp-json\/wp\/v2\/tags?post=7555"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}