7LY1

Crystal structure of Pseudomonas aeruginosa PBP3 in complex with vaborbactam

7LY1 の概要

• エントリーDOI: 10.2210/pdb7ly1/pdb
• 分子名称: Peptidoglycan D,D-transpeptidase FtsI, Vaborbactam (3 entities in total)
• 機能のキーワード: pbp3, penicillin-binding protein, boronic acid inhibitor, hydrolase
• 由来する生物種: Pseudomonas aeruginosa
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 58626.59

構造登録者

van den Akker, F.,Kumar, V. (登録日: 2021-03-05, 公開日: 2021-09-01, 最終更新日: 2024-11-13)

主引用文献

Kumar, V.,Viviani, S.L.,Ismail, J.,Agarwal, S.,Bonomo, R.A.,van den Akker, F.
Structural analysis of the boronic acid beta-lactamase inhibitor vaborbactam binding to Pseudomonas aeruginosa penicillin-binding protein 3.
Plos One, 16:e0258359-e0258359, 2021

PubMed Abstract: Antimicrobial resistance (AMR) mediated by β-lactamases is the major and leading cause of resistance to penicillins and cephalosporins among Gram-negative bacteria. β-Lactamases, periplasmic enzymes that are widely distributed in the bacterial world, protect penicillin-binding proteins (PBPs), the major cell wall synthesizing enzymes, from inactivation by β-lactam antibiotics. Developing novel PBP inhibitors with a non-β-lactam scaffold could potentially evade this resistance mechanism. Based on the structural similarities between the evolutionary related serine β-lactamases and PBPs, we investigated whether the potent β-lactamase inhibitor, vaborbactam, could also form an acyl-enzyme complex with Pseudomonas aeruginosa PBP3. We found that this cyclic boronate, vaborbactam, inhibited PBP3 (IC50 of 262 μM), and its binding to PBP3 increased the protein thermal stability by about 2°C. Crystallographic analysis of the PBP3:vaborbactam complex reveals that vaborbactam forms a covalent bond with the catalytic S294. The amide moiety of vaborbactam hydrogen bonds with N351 and the backbone oxygen of T487. The carboxyl group of vaborbactam hydrogen bonds with T487, S485, and S349. The thiophene ring and cyclic boronate ring of vaborbactam form hydrophobic interactions, including with V333 and Y503. The active site of the vaborbactam-bound PBP3 harbors the often observed ligand-induced formation of the aromatic wall and hydrophobic bridge, yet the residues involved in this wall and bridge display much higher temperature factors compared to PBP3 structures bound to high-affinity β-lactams. These insights could form the basis for developing more potent novel cyclic boronate-based PBP inhibitors to inhibit these targets and overcome β-lactamases-mediated resistance mechanisms.

PubMed: 34653211
DOI: 10.1371/journal.pone.0258359

実験手法

X-RAY DIFFRACTION (2.2 Å)