{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T23:32:25Z","timestamp":1791588745047,"version":"4.3.4"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T00:00:00Z","timestamp":1751587200000},"content-version":"vor","delay-in-days":14,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005725","name":"CHDI Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005725","id-type":"DOI","asserted-by":"publisher"}]},{"name":"CHDI Management"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,6,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Human and mouse genetic studies have demonstrated a role for DNA mismatch repair (MMR) molecular machines in modulating the rate of somatic expansion of the huntingtin (HTT) CAG repeats, and onset and progression of Huntington's Disease (HD). MutS\u03b2, a key component of the MMR pathway, is a heterodimeric protein of MSH2 and MSH3 that recognizes and initiates the repair of extrahelical DNA extrusions. Loss-of-function of mouse Msh3 and reduced-expression alleles of human MSH3 lead to slower rates of somatic expansion and delayed disease onset in humans, signifying MSH3 as a promising therapeutic target for HD. Here we report biochemical and cryo-electron microscopy analyses of human MutS\u03b2, demonstrating MutS\u03b2 undergoes conformational changes induced by nucleotide and DNA binding. We present multiple conformations of MutS\u03b2 including the DNA-free MutS\u03b2 compatible with precisely complementary base-paired homoduplex DNA binding, two distinct structures of MutS\u03b2 bound to (CAG)2 DNA, a sliding clamp form and a DNA-unbound, ATP-bound conformation. Along with evidence for novel conformational states adopted by MutS\u03b2 to initiate the MMR cascade, these structures provide a foundation for structure-guided drug discovery.<\/jats:p>","DOI":"10.1093\/nar\/gkaf604","type":"journal-article","created":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T07:58:26Z","timestamp":1750319906000},"source":"Crossref","is-referenced-by-count":5,"title":["Elucidation of multiple high-resolution states of human MutS\u03b2 by cryo-EM reveals interplay between ATP\/ADP binding and heteroduplex DNA recognition"],"prefix":"10.1093","volume":"53","author":[{"given":"Jung-Hoon","family":"Lee","sequence":"first","affiliation":[{"name":"Proteros biostructures GmbH, Bunsenstr 7a , Martinsried , 82152 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maren","family":"Thomsen","sequence":"additional","affiliation":[{"name":"Proteros biostructures GmbH, Bunsenstr 7a , Martinsried , 82152 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