3UD5

Crystal structure of E. coli HPPK in complex with bisubstrate analogue inhibitor J1A

3UD5 の概要

• エントリーDOI: 10.2210/pdb3ud5/pdb
• 関連するPDBエントリー: 1EX8 3UDE 3UDV
• 分子名称: 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine pyrophosphokinase, 5'-S-[1-(2-{[(2-amino-4-oxo-3,4-dihydropteridin-6-yl)methyl]amino}ethyl)piperidin-4-yl]-5'-thioadenosine, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: alpha beta, kinase, atp binding, pyrophosphoryl transfer, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Escherichia coli
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 18675.32

構造登録者

Shaw, G.,Shi, G.,Ji, X. (登録日: 2011-10-27, 公開日: 2012-01-04, 最終更新日: 2023-09-13)

主引用文献

Shi, G.,Shaw, G.,Liang, Y.H.,Subburaman, P.,Li, Y.,Wu, Y.,Yan, H.,Ji, X.
Bisubstrate analogue inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase: New design with improved properties.
Bioorg.Med.Chem., 20:47-57, 2012

PubMed Abstract: 6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), a key enzyme in the folate biosynthetic pathway, catalyzes the pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin. The enzyme is essential for microorganisms, is absent from humans, and is not the target for any existing antibiotics. Therefore, HPPK is an attractive target for developing novel antimicrobial agents. Previously, we characterized the reaction trajectory of HPPK-catalyzed pyrophosphoryl transfer and synthesized a series of bisubstrate analog inhibitors of the enzyme by linking 6-hydroxymethylpterin to adenosine through 2, 3, or 4 phosphate groups. Here, we report a new generation of bisubstrate analog inhibitors. To improve protein binding and linker properties of such inhibitors, we have replaced the pterin moiety with 7,7-dimethyl-7,8-dihydropterin and the phosphate bridge with a piperidine linked thioether. We have synthesized the new inhibitors, measured their K(d) and IC(50) values, determined their crystal structures in complex with HPPK, and established their structure-activity relationship. 6-Carboxylic acid ethyl ester-7,7-dimethyl-7,8-dihydropterin, a novel intermediate that we developed recently for easy derivatization at position 6 of 7,7-dimethyl-7,8-dihydropterin, offers a much high yield for the synthesis of bisubstrate analogs than that of previously established procedure.

PubMed: 22169600
DOI: 10.1016/j.bmc.2011.11.032

実験手法

X-RAY DIFFRACTION (2 Å)