6DYY

Crystal structure of Helicobacter pylori 5'-methylthioadenosine/S-adenosyl homocysteine nucleosidase (MTAN) complexed with (3R,4S)-1-((4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)-4-(((3-(1-butyl-1H-1,2,3-triazol-4-yl)propyl)thio)methyl)pyrrolidin-3-ol

6DYY の概要

• エントリーDOI: 10.2210/pdb6dyy/pdb
• 分子名称: 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase, 1,2-ETHANEDIOL, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: mtan enzyme, duodenal ulcers, stomach cancer, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Helicobacter pylori (Campylobacter pylori)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 109808.97

構造登録者

Harijan, R.K.,Ducati, R.G.,Bonanno, J.B.,Almo, S.C.,Schramm, V.L. (登録日: 2018-07-02, 公開日: 2019-03-20, 最終更新日: 2023-10-11)

主引用文献

Harijan, R.K.,Hoff, O.,Ducati, R.G.,Firestone, R.S.,Hirsch, B.M.,Evans, G.B.,Schramm, V.L.,Tyler, P.C.
Selective Inhibitors of Helicobacter pylori Methylthioadenosine Nucleosidase and Human Methylthioadenosine Phosphorylase.
J. Med. Chem., 62:3286-3296, 2019

PubMed Abstract: Bacterial 5'-methylthioadenosine/ S-adenosylhomocysteine nucleosidase (MTAN) hydrolyzes adenine from its substrates to form S-methyl-5-thioribose and S-ribosyl-l-homocysteine. MTANs are involved in quorum sensing, menaquinone synthesis, and 5'-methylthioadenosine recycling to S-adenosylmethionine. Helicobacter pylori uses MTAN in its unusual menaquinone pathway, making H. pylori MTAN a target for antibiotic development. Human 5'-methylthioadenosine phosphorylase (MTAP), a reported anticancer target, catalyzes phosphorolysis of 5'-methylthioadenosine to salvage S-adenosylmethionine. Transition-state analogues designed for HpMTAN and MTAP show significant overlap in specificity. Fifteen unique transition-state analogues are described here and are used to explore inhibitor specificity. Several analogues of HpMTAN bind in the picomolar range while inhibiting human MTAP with orders of magnitude weaker affinity. Structural analysis of HpMTAN shows inhibitors extending through a hydrophobic channel to the protein surface. The more enclosed catalytic sites of human MTAP require the inhibitors to adopt a folded structure, displacing the phosphate nucleophile from the catalytic site.

PubMed: 30860833
DOI: 10.1021/acs.jmedchem.8b01642

実験手法

X-RAY DIFFRACTION (1.61 Å)