Structural and dynamic features of the MutT protein in the recognition of nucleotides with the mutagenic 8-oxoguanine base

Teruya Nakamura, Sachiko Meshitsuka, Seiju Kitagawa, Nanase Abe, Junichi Yamada, Tetsuya Ishino, Hiroaki Nakano, Teruhisa Tsuzuki, Takefumi Doi, Yuji Kobayashi, Satoshi Fujii, Mutsuo Sejiguchi, Yuriko Yamagata

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)

Abstract

Escherichia coli MutT hydrolyzes 8-oxo-dGTP to 8-oxo-dGMP, an event that can prevent the misincorporation of 8-oxoguanine opposite adenine in DNA. Of the several enzymes that recognize 8-oxoguanine, MutT exhibits high substrate specificity for 8-oxoguanine nucleotides; however, the structural basis for this specificity is unknown. The crystal structures of MutT in the apo and holo forms and in the binary and ternary forms complexed with the product 8-oxo-dGMP and 8-oxo-dGMP plus Mn2+, respectively, were determined. MutT strictly recognizes the overall conformation of 8-oxo-dGMP through a number of hydrogen bonds. This recognition mode revealed that 8-oxoguanine nucleotides are discriminated from guanine nucleotides by not only the hydrogen bond between the N7-H and Oδ (N119) atoms but also by the syn glycosidic conformation that 8-oxoguanine nucleotides prefer. Nevertheless, these discrimination factors cannot by themselves explain the roughly 34,000-fold difference between the affinity of MutT for 8-oxo-dGMP and dGMP. When the binary complex of MutT with 8-oxo-dGMP is compared with the ligand-free form, ordering and considerable movement of the flexible loops surrounding 8-oxo-dGMP in the binary complex are observed. These results indicate that MutT specifically recognizes 8-oxoguanine nucleotides by the ligand-induced conformational change.

Original languageEnglish
Pages (from-to)444-452
Number of pages9
JournalJournal of Biological Chemistry
Volume285
Issue number1
DOIs
Publication statusPublished - Jan 1 2010

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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