4yoq
From Proteopedia
Crystal Structure of MutY bound to its anti-substrate
Structural highlights
FunctionMUTY_GEOSE Base excision repair (BER) glycosylase that initiates repair of A:oxoG to C:G by removing the inappropriately paired adenine base from the DNA backbone, generating an abasic site product (PubMed:25995449) (PubMed:14961129). 8-oxoguanine (oxoG) is a genotoxic DNA lesion resulting from oxidation of guanine; this residue is misread by replicative DNA polymerases, that insert adenine instead of cytosine opposite the oxidized damaged base. Shows a powerful dicrimination of A versus C, since it does not cleave cytosine in oxoG:C pairs (PubMed:25995449). May also be able to remove adenine from A:G mispairs, although this activity may not be physiologically relevant (PubMed:14961129).[1] [2] Publication Abstract from PubMedThe highly mutagenic A:oxoG base-pair in DNA most frequently arises by aberrant replication of the primary oxidative lesion C:oxoG. This lesion is particularly insidious, because neither of its constituent nucleobases faithfully transmit genetic information from the original C:G base-pair. Repair of A:oxoG is initiated by adenine DNA glycosylase which catalyzes hydrolytic cleavage of the aberrant A nucleobase from the DNA backbone. These enzymes, MutY in bacteria and hMYH in humans, scrupulously avoid processing of C:oxoG, because cleavage of the C residue in C:oxoG would actually promote mutagenic conversion to A:oxoG. Here we analyze the structural basis for rejection of C:oxoG by MutY, using a synthetic crystallography approach to capture the enzyme in the process of inspecting the C:oxoG anti-substrate, with which it ordinarily binds only fleetingly. We find that MutY uses two distinct strategies to avoid presentation of C to the enzyme active site. Firstly, MutY possesses an exo-site that serves as a decoy for C, and secondly, repulsive forces with a key active site residue prevent stable insertion of C into the nucleobase-recognition pocket within the enzyme active site. Structural Basis for Avoidance of Promutagenic DNA Repair by MutY Adenine DNA Glycosylase.,Wang L, Lee SJ, Verdine G J Biol Chem. 2015 May 20. pii: jbc.M115.657866. PMID:25995449[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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