Lamers M H, Perrakis A, Enzlin J H, Winterwerp H H, de Wind N, Sixma T K
Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam.
Nature. 2000 Oct 12;407(6805):711-7. doi: 10.1038/35037523.
DNA mismatch repair ensures genomic integrity on DNA replication. Recognition of a DNA mismatch by a dimeric MutS protein initiates a cascade of reactions and results in repair of the newly synthesized strand; however, details of the molecular mechanism remain controversial. Here we present the crystal structure at 2.2 A of MutS from Escherichia coli bound to a G x T mismatch. The two MutS monomers have different conformations and form a heterodimer at the structural level. Only one monomer recognizes the mismatch specifically and has ADP bound. Mismatch recognition occurs by extensive minor groove interactions causing unusual base pairing and kinking of the DNA. Nonspecific major groove DNA-binding domains from both monomers embrace the DNA in a clamp-like structure. The interleaved nucleotide-binding sites are located far from the DNA. Mutations in human MutS alpha (MSH2/MSH6) that lead to hereditary predisposition for cancer, such as hereditary non-polyposis colorectal cancer, can be mapped to this crystal structure.
DNA错配修复确保DNA复制时的基因组完整性。二聚体MutS蛋白识别DNA错配会引发一系列反应，并导致新合成链的修复；然而，分子机制的细节仍存在争议。在此，我们展示了来自大肠杆菌的MutS与G×T错配结合时2.2埃分辨率的晶体结构。两个MutS单体具有不同的构象，并在结构层面形成异二聚体。只有一个单体特异性识别错配并结合ADP。错配识别通过广泛的小沟相互作用发生，导致DNA的异常碱基配对和扭结。两个单体的非特异性大沟DNA结合结构域以钳状结构环绕DNA。交错的核苷酸结合位点远离DNA。导致遗传性癌症易感性的人类MutSα（MSH2/MSH6）突变，如遗传性非息肉病性结直肠癌，可映射到该晶体结构上。
