1T39

HUMAN O6-ALKYLGUANINE-DNA ALKYLTRANSFERASE COVALENTLY CROSSLINKED TO DNA

1T39 の概要

• エントリーDOI: 10.2210/pdb1t39/pdb
• 関連するPDBエントリー: 1EH6 1EH7 1EH8 1T38
• 分子名称: 5'-D(*GP*CP*CP*AP*TP*GP*(E1X)P*CP*TP*AP*GP*TP*A)-3', 5'-D(*TP*AP*CP*TP*AP*GP*CP*CP*AP*TP*GP*GP*C)-3', Methylated-DNA--protein-cysteine methyltransferase (3 entities in total)
• 機能のキーワード: alkyltransferase, methyltransferase, dna repair, helix-turn-helix, transferase-dna complex, transferase/dna
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus: P16455
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 56655.41

構造登録者

Daniels, D.S.,Woo, T.T.,Luu, K.X.,Noll, D.M.,Clarke, N.D.,Pegg, A.E.,Tainer, J.A. (登録日: 2004-04-25, 公開日: 2004-07-13, 最終更新日: 2024-10-30)

主引用文献

Daniels, D.S.,Woo, T.T.,Luu, K.X.,Noll, D.M.,Clarke, N.D.,Pegg, A.E.,Tainer, J.A.
DNA binding and nucleotide flipping by the human DNA repair protein AGT.
Nat.Struct.Mol.Biol., 11:714-720, 2004

PubMed Abstract: O(6)-alkylguanine-DNA alkyltransferase (AGT), or O(6)-methylguanine-DNA methyltransferase (MGMT), prevents mutations and apoptosis resulting from alkylation damage to guanines. AGT irreversibly transfers the alkyl lesion to an active site cysteine in a stoichiometric, direct damage reversal pathway. AGT expression therefore elicits tumor resistance to alkylating chemotherapies, and AGT inhibitors are in clinical trials. We report here structures of human AGT in complex with double-stranded DNA containing the biological substrate O(6)-methylguanine or crosslinked to the mechanistic inhibitor N(1),O(6)-ethanoxanthosine. The prototypical DNA major groove-binding helix-turn-helix (HTH) motif mediates unprecedented minor groove DNA binding. This binding architecture has advantages for DNA repair and nucleotide flipping, and provides a paradigm for HTH interactions in sequence-independent DNA-binding proteins like RecQ and BRCA2. Structural and biochemical results further support an unpredicted role for Tyr114 in nucleotide flipping through phosphate rotation and an efficient kinetic mechanism for locating alkylated bases.

PubMed: 15221026
DOI: 10.1038/nsmb791

実験手法

X-RAY DIFFRACTION (3.3 Å)