6TD0

Crystal structure of vaborbactam bound to KPC-2

6TD0 の概要

• エントリーDOI: 10.2210/pdb6td0/pdb
• 分子名称: Carbapenem-hydrolyzing beta-lactamase KPC, Vaborbactam, GLYCEROL, ... (5 entities in total)
• 機能のキーワード: inhibitor, boronate, beta-lactamase, antimicrobial protein
• 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: 31768.27

構造登録者

Tooke, C.L.,Hinchliffe, P.,Spencer, J. (登録日: 2019-11-07, 公開日: 2020-01-22, 最終更新日: 2024-11-13)

主引用文献

Tooke, C.L.,Hinchliffe, P.,Krajnc, A.,Mulholland, A.J.,Brem, J.,Schofield, C.J.,Spencer, J.
Cyclic boronates as versatile scaffolds for KPC-2 beta-lactamase inhibition.
Rsc Med Chem, 11:491-496, 2020

PubMed Abstract: carbapenemase-2 (KPC-2) is a serine-β-lactamase (SBL) capable of hydrolysing almost all β-lactam antibiotics. We compare KPC-2 inhibition by vaborbactam, a clinically-approved monocyclic boronate, and VNRX-5133 (taniborbactam), a bicyclic boronate in late-stage clinical development. Vaborbactam inhibition is slowly reversible, whereas taniborbactam has an off-rate indicating essentially irreversible complex formation and a 15-fold higher on-rate, although both potentiate β-lactam activity against KPC-2-expressing . High resolution X-ray crystal structures reveal closely related binding modes for both inhibitors to KPC-2, with differences apparent only in positioning of the endocyclic boronate ester oxygen. The results indicate the bicyclic boronate scaffold as both an efficient, long-lasting, KPC-2 inhibitor and capable of supporting further iterations that may improve potency against specific enzyme targets and pre-empt the emergence of inhibitor resistant KPC-2 variants.

PubMed: 33479650
DOI: 10.1039/c9md00557a

実験手法

X-RAY DIFFRACTION (0.99 Å)