8SKP

X-ray structure of the NDM-4 beta-lactamase from Klebsiella pneumonia in complex with 1-hydroxypyridine-2(1H)-thione-6-carboxylic acid

8SKP の概要

• エントリーDOI: 10.2210/pdb8skp/pdb
• 関連するPDBエントリー: 8sk2 8sko
• 分子名称: Metallo-beta-lactamase type 2, ZINC ION, 1-hydroxy-6-sulfanylidene-1,6-dihydropyridine-2-carboxylic acid, ... (5 entities in total)
• 機能のキーワード: beta-lactamase, hydrolase, metallo-enzyme, hydrolase-inhibitor complex, hydrolase/inhibitor
• 由来する生物種: Klebsiella pneumoniae
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 24592.28

構造登録者

Thoden, J.B.,Holden, H.M. (登録日: 2023-04-20, 公開日: 2023-08-23, 最終更新日: 2023-10-04)

主引用文献

Thoden, J.B.,Benin, B.M.,Priebe, A.,Shin, W.S.,Muthyala, R.,Sham, Y.Y.,Holden, H.M.
Characterization of a novel inhibitor for the New Delhi metallo-beta-lactamase-4: Implications for drug design and combating bacterial drug resistance.
J.Biol.Chem., 299:105135-105135, 2023

PubMed Abstract: The bacterial metallo-β-lactamases (MBLs) catalyze the inactivation of β-lactam antibiotics. Identifying novel pharmacophores remains crucial for the clinical development of additional MBL inhibitors. Previously, 1-hydroxypyridine-2(1H)-thione-6-carboxylic acid, hereafter referred to as 1,2-HPT-6-COOH, was reported as a low cytotoxic nanomolar β-lactamase inhibitor of Verona-integron-encoded metallo-β-lactamase 2, capable of rescuing β-lactam antibiotic activity. In this study, we explore its exact mechanism of inhibition and the extent of its activity through structural characterization of its binding to New Delhi metallo-β-lactamase 4 (NDM-4) and its inhibitory activity against both NDM-1 and NDM-4. Of all the structure-validated MBL inhibitors available, 1,2-HPT-6-COOH is the first discovered compound capable of forming an octahedral coordination sphere with Zn2 of the binuclear metal center. This unexpected mechanism of action provides important insight for the further optimization of 1,2-HPT-6-COOH and the identification of additional pharmacophores for MBL inhibition.

PubMed: 37549809
DOI: 10.1016/j.jbc.2023.105135

実験手法

X-RAY DIFFRACTION (1.3 Å)