{"id":3163,"date":"2025-12-02T12:53:42","date_gmt":"2025-12-02T03:53:42","guid":{"rendered":"https:\/\/pf-form.kek.jp\/sbrc\/?p=3163"},"modified":"2025-12-02T12:54:33","modified_gmt":"2025-12-02T03:54:33","slug":"seminar30","status":"publish","type":"post","link":"https:\/\/pf-form.kek.jp\/sbrc\/seminar30\/","title":{"rendered":"SBRC International Cryo-EM Seminar No.30"},"content":{"rendered":"\n<blockquote class=\"wp-block-quote is-layout-flow wp-block-quote-is-layout-flow\">\n<h2 class=\"wp-block-heading\">\u201cTargeting Asparagine Synthetase: Structural and Cellular Mechanisms of the Small-Molecule Inhibitor ASX-173\u201d<\/h2>\n<\/blockquote>\n\n\n\n<p> _<\/p>\n\n\n\n<h2 class=\"wp-block-heading\">Date and Time<\/h2>\n\n\n\n<p style=\"font-size:25px\">4:00 PM &#8211; 5:30 PM Wednesday, December 17<sup>th<\/sup>, 2025<\/p>\n\n\n\n<p><\/p>\n\n\n\n<h2 class=\"wp-block-heading\">Location<\/h2>\n\n\n\n<p style=\"font-size:25px\">Hybrid\uff08CryoEM building and Zoom\uff09<\/p>\n\n\n\n<hr class=\"wp-block-separator has-alpha-channel-opacity\" \/>\n\n\n\n<h2 class=\"wp-block-heading\" style=\"font-size:30px\">Speaker<\/h2>\n\n\n<div class=\"wp-block-image is-resized\">\n<figure class=\"alignleft size-large\"><img loading=\"lazy\" decoding=\"async\" width=\"644\" height=\"766\" src=\"https:\/\/pf-form.kek.jp\/sbrc\/wp-content\/uploads\/sites\/39\/2023\/11\/Takagi_photo-644x766.jpg\" alt=\"\" class=\"wp-image-1827\" style=\"aspect-ratio:0.8407310704960835;width:228px;height:auto\" srcset=\"https:\/\/pf-form.kek.jp\/sbrc\/wp-content\/uploads\/sites\/39\/2023\/11\/Takagi_photo-644x766.jpg 644w, https:\/\/pf-form.kek.jp\/sbrc\/wp-content\/uploads\/sites\/39\/2023\/11\/Takagi_photo-252x300.jpg 252w, https:\/\/pf-form.kek.jp\/sbrc\/wp-content\/uploads\/sites\/39\/2023\/11\/Takagi_photo-768x913.jpg 768w, https:\/\/pf-form.kek.jp\/sbrc\/wp-content\/uploads\/sites\/39\/2023\/11\/Takagi_photo.jpg 1044w\" sizes=\"auto, (max-width: 644px) 100vw, 644px\" \/><\/figure>\n<\/div>\n\n\n<h2 class=\"wp-block-heading\" style=\"font-size:28px\">Yuichiro H. Takagi, Ph.D.<\/h2>\n\n\n\n<p>Associate Professor<br>Scientific advisor for cryo-EM&nbsp;<br>Department of Biochemistry and&nbsp;Molecular Biology<br>Indiana University School of Medicine<\/p>\n\n\n\n<p><a href=\"https:\/\/twitter.com\/LabTakagi\" data-type=\"link\" data-id=\"https:\/\/twitter.com\/LabTakagi\">Takagi Lab<\/a><\/p>\n\n\n\n<p><\/p>\n\n\n\n<hr class=\"wp-block-separator has-css-opacity is-style-dots\" \/>\n\n\n\n<h2 class=\"wp-block-heading\">Abstract<\/h2>\n\n\n\n<p>Targeting asparagine metabolism is a promising strategy for treating asparaginase-resistant acute lymphoblastic leukemia (ALL), sarcoma, and potentially other solid tumors. Here, we characterize the molecular mechanism by which a cell-penetrable small molecule, ASX-173, inhibits human asparagine synthetase (ASNS), the enzyme that catalyzes intracellular asparagine biosynthesis. ASX-173 reduces cellular asparagine levels, induces the integrated stress response (ISR), and reduces cell growth in HEK-293A cells. A cryo-EM structure reveals that ASX-173 engages a unique, hydrophobic pocket formed by AMP, Mg2+, and pyrophosphate in the C-terminal synthetase domain of ASNS, thereby enabling multivalent, high-affinity binding. Based on in vitro kinetic and thermal shift assays, we find that ASX-173 binds to the ASNS\/Mg2+\/ATP complex and is therefore a rare example of an uncompetitive enzyme inhibitor with potential therapeutic use. These findings provide a structural and mechanistic basis for targeting ASNS with small molecules, which have application in treating cancer and other human diseases.<\/p>\n\n\n\n<p><\/p>\n\n\n\n<hr class=\"wp-block-separator has-css-opacity is-style-dots\" \/>\n\n\n\n<h2 class=\"wp-block-heading has-text-align-center has-white-color has-cyan-bluish-gray-background-color has-text-color has-background\"><a href=\"https:\/\/pf-form.kek.jp\/sbrc\/registration-for\/\" data-type=\"link\" data-id=\"https:\/\/pf-form.kek.jp\/sbrc\/registration_for_international_seminar\/\" target=\"_blank\" rel=\"noreferrer noopener\">Click here to apply<\/a><\/h2>\n","protected":false},"excerpt":{"rendered":"<p>\u201cTargeting Asparagine Synthetase: Structural and Cellular Mechanisms of the Small-Molecule Inhibitor ASX-173\u201d  [&hellip;]<\/p>\n","protected":false},"author":26,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[3],"tags":[],"class_list":["post-3163","post","type-post","status-publish","format-standard","hentry","category-kek-cryoem"],"_links":{"self":[{"href":"https:\/\/pf-form.kek.jp\/sbrc\/wp-json\/wp\/v2\/posts\/3163","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/pf-form.kek.jp\/sbrc\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/pf-form.kek.jp\/sbrc\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/pf-form.kek.jp\/sbrc\/wp-json\/wp\/v2\/users\/26"}],"replies":[{"embeddable":true,"href":"https:\/\/pf-form.kek.jp\/sbrc\/wp-json\/wp\/v2\/comments?post=3163"}],"version-history":[{"count":2,"href":"https:\/\/pf-form.kek.jp\/sbrc\/wp-json\/wp\/v2\/posts\/3163\/revisions"}],"predecessor-version":[{"id":3167,"href":"https:\/\/pf-form.kek.jp\/sbrc\/wp-json\/wp\/v2\/posts\/3163\/revisions\/3167"}],"wp:attachment":[{"href":"https:\/\/pf-form.kek.jp\/sbrc\/wp-json\/wp\/v2\/media?parent=3163"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/pf-form.kek.jp\/sbrc\/wp-json\/wp\/v2\/categories?post=3163"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/pf-form.kek.jp\/sbrc\/wp-json\/wp\/v2\/tags?post=3163"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}