7KDO

Crystal structure of Escherichia coli HPPK in complex with bisubstrate inhibitor HP-73

7KDO の概要

• エントリーDOI: 10.2210/pdb7kdo/pdb
• 分子名称: 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine pyrophosphokinase, 5'-S-[(2R,4R)-1-{2-[(2-amino-7,7-dimethyl-4-oxo-3,4,7,8-tetrahydropteridine-6-carbonyl)amino]ethyl}-2-carboxypiperidin-4-yl]-5'-thioadenosine (3 entities in total)
• 機能のキーワード: alpha beta, transferase, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Escherichia coli (strain K12)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 18639.25

構造登録者

Shaw, G.X.,Shi, G.,Ji, X. (登録日: 2020-10-09, 公開日: 2020-12-02, 最終更新日: 2023-10-18)

主引用文献

Shi, G.,Shaw, G.X.,Zhu, F.,Tarasov, S.G.,Ji, X.
Bisubstrate inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase: Transition state analogs for high affinity binding.
Bioorg.Med.Chem., 29:115847-115847, 2021

PubMed Abstract: 6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) is a key enzyme in the folate biosynthesis pathway. It catalyzes pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin (HP). HPPK is essential for microorganisms but absent in mammals; therefore, it is an attractive target for developing novel antimicrobial agents. Previously, based on our studies of the structure and mechanism of HPPK, we created first-generation bisubstrate inhibitors by linking 6-hydroxymethylpterin to adenosine through phosphate groups, and developed second-generation inhibitors by replacing the phosphate bridge with a linkage that contains a piperidine moiety. Here, we report third-generation inhibitors designed based on the piperidine-containing inhibitor, mimicking the transition state. We synthesized two such inhibitors, characterized their protein-binding and enzyme inhibition properties, and determined their crystal structures in complex with HPPK, advancing the development of such bisubstrate analog inhibitors.

PubMed: 33199204
DOI: 10.1016/j.bmc.2020.115847

実験手法

X-RAY DIFFRACTION (1.6 Å)