{"id":556,"date":"2020-01-04T08:40:50","date_gmt":"2020-01-04T08:40:50","guid":{"rendered":"https:\/\/zobio.com\/online\/?p=556"},"modified":"2023-03-09T09:38:01","modified_gmt":"2023-03-09T09:38:01","slug":"mettl3-mettl14-an-epitranscriptomic-writer-complex","status":"publish","type":"post","link":"https:\/\/zobio.com\/online\/cases\/mettl3-mettl14-an-epitranscriptomic-writer-complex\/","title":{"rendered":"Mettl3\/Mettl14 \u2013 An epitranscriptomic writer complex"},"content":{"rendered":"

Mettl3\/Mettl14 \u2013 An epitranscriptomic writer complex<\/h2>\n
\n\t

Challenge
\n<\/strong>Mettl3\/Mettl14 is a large (90 kDa) heterodimeric \u201cwriter\u201d complex that uses S-adenosyl methionine (SAM) as a cofactor. \u00a0Identifying low affinity, validated fragment hits in the large amount of electron density derived from X-ray diffraction data was extremely difficult.<\/p>\n

Solution
\n<\/b>X-ray crystallography provides the necessary high resolution structural data needed to efficiently elaborate hits from fragment or HTS campaigns. However, even highly validated fragment hits typically exhibit low affinity (100s to 1000s of \u00b5M). As a result, the occupancy of ligand binding sites in the crystal may be substantially less than 100%, which degrades the quality of the electron density of the fragment. Moreover, fragments are small and overall somewhat symmetric, further reducing identifiable features of their electron density.<\/p>\n

We set up a solution competition binding experiment using NMR as a readout to focus on fragments that bind at the SAM site. We quickly found a fragment containing a CF3<\/sub> moiety that bound at the SAM site. We could then use 19<\/sup>F NMR studies as a clean, sensitive and fast approach<\/span> to reveal other ligands that bound at the same site. Once we were certain of the binding site, we were readily able to identify electron density at the SAM site and confidently assign it to the ligand.<\/p>\n

Achievements
\n<\/strong>We developed a highly efficient structure pipeline capable of determining up to 10 sub 2\u00c5 structures per month which has been the basis for elaborating fragment hits to cellular activity and beyond. Multiple chemotypes are promising, allowing for a robust hit-to-lead campaign.<\/p>\n<\/div>\n<\/div><\/div><\/div><\/div><\/div><\/div><\/div>","protected":false},"excerpt":{"rendered":"

Challenge<\/b>
\nMettl3\/Mettl14 is a large (90 kDa) heterodimeric \u201cwriter\u201d complex that uses S-adenosyl methionine (SAM) as a cofactor. Identifying low affinity, validated fragment hits in the large amount of electron density derived from X-ray diffraction data was extremely difficult.<\/p>\n

Achievements<\/b>
\nWe developed a highly efficient structure pipeline capable of determining up to 10 sub 2\u00c5 structures per month which has been the basis for elaborating fragment hits to cellular activity and beyond. Multiple chemotypes are promising, allowing for a robust hit-to-lead campaign.<\/p>\n","protected":false},"author":3,"featured_media":3986,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"gpsa_enabled":false,"gpsa_required_form_ids":[],"gpsa_require_unique_form_submission":false,"gpsa_access_behavior":"show_message","gpsa_form_redirect_path":"","gpsa_requires_access_message":"","gpsa_access":[],"gpsa_content_loading_message":"","footnotes":""},"categories":[5],"tags":[],"class_list":["post-556","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-cases"],"yoast_head":"\nMettl3\/Mettl14 \u2013 An epitranscriptomic writer complex - ZoBio - Drug Discovery Technology<\/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:\/\/zobio.com\/online\/cases\/mettl3-mettl14-an-epitranscriptomic-writer-complex\/\" \/>\n<meta property=\"og:locale\" content=\"en_GB\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Mettl3\/Mettl14 \u2013 An epitranscriptomic writer complex - ZoBio - Drug Discovery Technology\" \/>\n<meta property=\"og:description\" content=\"Challenge Mettl3\/Mettl14 is a large (90 kDa) heterodimeric \u201cwriter\u201d complex that uses S-adenosyl methionine (SAM) as a cofactor. Identifying low affinity, validated fragment hits in the large amount of electron density derived from X-ray diffraction data was extremely difficult. Achievements We developed a highly efficient structure pipeline capable of determining up to 10 sub 2\u00c5 structures per month which has been the basis for elaborating fragment hits to cellular activity and beyond. 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