4bhc | pdb_00004bhc
CRYSTAL STRUCTURE OF THE M. TUBERCULOSIS O6-METHYLGUANINE METHYLTRANSFERASE R37L VARIANT
Structural highlights
Function[OGT_MYCTU] Involved in the cellular defense against the biological effects of O6-methylguanine (O6-MeG) in DNA. Repairs alkylated guanine in DNA by stoichiometrically transferring the alkyl group at the O-6 position to a cysteine residue in the enzyme. This is a suicide reaction: the enzyme is irreversibly inactivated (By similarity). Publication Abstract from PubMedM. tuberculosis displays a remarkable genetic stability despite continuous exposure to the hostile environment represented by the host's infected macrophages. Similarly to other organisms, M. tuberculosis possesses multiple systems to contrast the harmful potential of DNA alkylation. In particular, the suicidal enzyme O6-methylguanine-DNA methyltransferase (OGT) is responsible for the direct repair of O6-alkylguanine in double-stranded DNA and is therefore supposed to play a central role in protecting the mycobacterial genome from the risk of G:C to A:T transition mutations. Notably, a number of geographically widely distributed M. tuberculosis strains shows non-synonymous SNPs in their OGT encoding gene, leading to amino acid substitutions at position 15 (T15S) or 37 (R37L) of the N-terminal domain of the corresponding protein. However, the role of these mutations in M. tuberculosis pathogenesis is unknown.We describe here the in vitro characterization of M. tuberculosis OGT (MtOGT) and of two point-mutated versions of the protein mimicking the naturally occurring ones, revealing that both mutated proteins are impaired in their activity as a consequence of their lower affinity for alkylated DNA with respect to the wild-type protein. The analysis of the crystal structures of MtOGT and MtOGT-R37L confirms the high level of structural conservation featuring members of this protein family and provides cues to understand the molecular bases of the reduced affinity for the natural substrate displayed by mutated MtOGT. Our in vitro results could contribute to validate the inferred participation of mutated OGTs to M. tuberculosis phylogeny and biology. BIOCHEMICAL AND STRUCTURAL STUDIES ON THE M. TUBERCULOSIS O6-METHYLGUANINE METHYLTRANSFERASE AND MUTATED VARIANTS.,Miggiano R, Casazza V, Garavaglia S, Ciaramella M, Perugino G, Rizzi M, Rossi F J Bacteriol. 2013 Apr 5. PMID:23564173[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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