{"id":241709,"date":"2026-07-28T16:08:41","date_gmt":"2026-07-28T21:08:41","guid":{"rendered":"https:\/\/lifeboat.com\/blog\/2026\/07\/structure-and-evolutionguided-design-of-minimal-rnaguided-nucleases"},"modified":"2026-07-28T16:08:41","modified_gmt":"2026-07-28T21:08:41","slug":"structure-and-evolutionguided-design-of-minimal-rnaguided-nucleases","status":"publish","type":"post","link":"https:\/\/lifeboat.com\/blog\/2026\/07\/structure-and-evolutionguided-design-of-minimal-rnaguided-nucleases","title":{"rendered":"Structure and evolutionguided design of minimal RNAguided nucleases"},"content":{"rendered":"<p><a class=\"aligncenter blog-photo\" href=\"https:\/\/lifeboat.com\/blog.images\/structure-and-evolutionguided-design-of-minimal-rnaguided-nucleases2.jpg\"><\/a><\/p>\n<p>The design of RNA-guided nucleases with properties not limited by evolution can expand programmable genome-editing capabilities. However, generating diverse multidomain proteins with robust enzymatic properties remains challenging. Here, we use a protein design strategy that couples a structure-guided inverse-folding model with evolution-informed residue constraints to generate active, divergent variants of TnpB, a minimal CRISPR-Cas12\u2013like nuclease, termed SynTnpBs. High-throughput screening of artificial intelligence\u2013generated variants yielded editors that retained or exceeded wild-type activity in bacterial, plant, and human cells. Cryo\u2013electron microscopy\u2013based structure determination of the most divergent variant revealed stabilizing contacts in the RNA\u2013DNA interfaces across conformations, demonstrating the design potential of this approach.<\/p>\n","protected":false},"excerpt":{"rendered":"<p>The design of RNA-guided nucleases with properties not limited by evolution can expand programmable genome-editing capabilities. However, generating diverse multidomain proteins with robust enzymatic properties remains challenging. Here, we use a protein design strategy that couples a structure-guided inverse-folding model with evolution-informed residue constraints to generate active, divergent variants of TnpB, a minimal CRISPR-Cas12\u2013like nuclease, [\u2026]<\/p>\n","protected":false},"author":662,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[11,6],"tags":[],"class_list":["post-241709","post","type-post","status-publish","format-standard","hentry","category-biotech-medical","category-robotics-ai"],"_links":{"self":[{"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/posts\/241709","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/users\/662"}],"replies":[{"embeddable":true,"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/comments?post=241709"}],"version-history":[{"count":0,"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/posts\/241709\/revisions"}],"wp:attachment":[{"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/media?parent=241709"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/categories?post=241709"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/tags?post=241709"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}