5FSL

MTH1 substrate recognition: Complex with a methylaminopurinone

5FSL の概要

• エントリーDOI: 10.2210/pdb5fsl/pdb
• 関連するPDBエントリー: 5FSI 5FSK 5FSM 5FSN 5FSO
• 分子名称: 7,8-DIHYDRO-8-OXOGUANINE TRIPHOSPHATASE, 9-METHYL-2-(METHYLAMINO)-1H-PURIN-6-ONE, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: hydrolase, nudt1
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Isoform p18: Cytoplasm. Isoform p26: Cytoplasm: P36639
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 18246.70

構造登録者

Nissink, J.W.M.,Bista, M.,Breed, J.,Carter, N.,Embrey, K.,Read, J.,Phillips, C.,Winter, J.J. (登録日: 2016-01-06, 公開日: 2016-07-20, 最終更新日: 2024-05-08)

主引用文献

Nissink, J.W.M.,Bista, M.,Breed, J.,Carter, N.,Embrey, K.,Read, J.,Winter-Holt, J.J.
Mth1 Substrate Recognition--an Example of Specific Promiscuity.
Plos One, 11:51154-, 2016

PubMed Abstract: MTH1 (NUDT1) is an oncologic target involved in the prevention of DNA damage. We investigate the way MTH1 recognises its substrates and present substrate-bound structures of MTH1 for 8-oxo-dGTP and 8-oxo-rATP as examples of novel strong and weak binding substrate motifs. Investigation of a small set of purine-like fragments using 2D NMR resulted in identification of a fragment with weak potency. The protein-ligand X-Ray structure of this fragment provides insight into the role of water molecules in substrate selectivity. Wider fragment screening by NMR resulted in three new protein structures exhibiting alternative binding configurations to the key Asp-Asp recognition element of the protein. These inhibitor binding modes demonstrate that MTH1 employs an intricate yet promiscuous mechanism of substrate anchoring through its Asp-Asp pharmacophore. The structures suggest that water-mediated interactions convey selectivity towards oxidized substrates over their non-oxidised counterparts, in particular by stabilization of a water molecule in a hydrophobic environment through hydrogen bonding. These findings may be useful in the design of inhibitors of MTH1.

PubMed: 26999531
DOI: 10.1371/JOURNAL.PONE.0151154

実験手法

X-RAY DIFFRACTION (1.24 Å)