2HHU

C:O6-methyl-guanine in the polymerase postinsertion site (-1 basepair position)

2HHU の概要

• エントリーDOI: 10.2210/pdb2hhu/pdb
• 関連するPDBエントリー: 2HHQ 2HHS 2HHT 2HHV 2HHW 2HHX 2HHY
• 関連するBIRD辞書のPRD_ID: PRD_900003
• 分子名称: 5'-D(*GP*CP*GP*AP*TP*CP*AP*GP*CP*CP*C)-3', 5'-D(*GP*TP*AP*CP*(6OG)P*GP*GP*CP*TP*GP*AP*TP*CP*GP*CP*A)-3', DNA Polymerase I, ... (8 entities in total)
• 機能のキーワード: dna polymerase i, dna replication, klenow fragment, protein-dna complex, o6-methyl-guanine, transferase-dna complex, transferase/dna
• 由来する生物種: Geobacillus stearothermophilus; 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 76063.67

構造登録者

Warren, J.J.,Forsberg, L.J.,Beese, L.S. (登録日: 2006-06-28, 公開日: 2006-12-12, 最終更新日: 2024-02-14)

主引用文献

Warren, J.J.,Forsberg, L.J.,Beese, L.S.
The structural basis for the mutagenicity of O6-methyl-guanine lesions.
Proc.Natl.Acad.Sci.Usa, 103:19701-19706, 2006

PubMed Abstract: Methylating agents are widespread environmental carcinogens that generate a broad spectrum of DNA damage. Methylation at the guanine O(6) position confers the greatest mutagenic and carcinogenic potential. DNA polymerases insert cytosine and thymine with similar efficiency opposite O(6)-methyl-guanine (O6MeG). We combined pre-steady-state kinetic analysis and a series of nine x-ray crystal structures to contrast the reaction pathways of accurate and mutagenic replication of O6MeG in a high-fidelity DNA polymerase from Bacillus stearothermophilus. Polymerases achieve substrate specificity by selecting for nucleotides with shape and hydrogen-bonding patterns that complement a canonical DNA template. Our structures reveal that both thymine and cytosine O6MeG base pairs evade proofreading by mimicking the essential molecular features of canonical substrates. The steric mimicry depends on stabilization of a rare cytosine tautomer in C.O6MeG-polymerase complexes. An unusual electrostatic interaction between O-methyl protons and a thymine carbonyl oxygen helps stabilize T.O6MeG pairs bound to DNA polymerase. Because DNA methylators constitute an important class of chemotherapeutic agents, the molecular mechanisms of replication of these DNA lesions are important for our understanding of both the genesis and treatment of cancer.

PubMed: 17179038
DOI: 10.1073/pnas.0609580103

実験手法

X-RAY DIFFRACTION (1.8 Å)