PDBsum entry 4zam

Hydrolase/hydrolase inhibitor

PDB id: 4zam

Contents

Protein chain

265 a.a.

Ligands

MA4 ×2

NXL

Waters ×283

PDB id:

4zam

Name:

Hydrolase/hydrolase inhibitor

Title:

Crystal structure of shv-1 beta-lactamase bound to avibactam

Structure:

Beta-lactamase shv-1. Chain: a. Fragment: unp residues 22-286. Synonym: pit-2. Engineered: yes

Source:

Klebsiella pneumoniae. Organism_taxid: 573. Gene: bla, shv1. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.42Å R-factor: 0.168 R-free: 0.193

Authors:

N.Krishnan,F.Van Den Akker

Key ref:

N.P.Krishnan et al. (2015). Inhibition of Klebsiella β-Lactamases (SHV-1 and KPC-2) by Avibactam: A Structural Study. Plos One, 10, e0136813. PubMed id: 26340563 DOI: 10.1371/journal.pone.0136813

Date:

13-Apr-15 Release date: 27-Jan-16

Protein chain

P0AD64  (BLA1_KLEPN) -  Beta-lactamase SHV-1 from Klebsiella pneumoniae

Seq: 286 a.a.

Struc: 265 a.a.

Enzyme reactions

• Enzyme class: E.C.3.5.2.6 - beta-lactamase.
• Pathway: Penicillin Biosynthesis and Metabolism
• Reaction: a beta-lactam + H2O = a substituted beta-amino acid
• Cofactor: Zn(2+)

DOI no: 10.1371/journal.pone.0136813

Plos One 10:e0136813 (2015)

PubMed id: 26340563

Inhibition of Klebsiella β-Lactamases (SHV-1 and KPC-2) by Avibactam: A Structural Study.

N.P.Krishnan, N.Q.Nguyen, K.M.Papp-Wallace, R.A.Bonomo, F.van den Akker.

ABSTRACT

β-Lactamase inhibition is an important clinical strategy in overcoming β-lactamase-mediated resistance to β-lactam antibiotics in Gram negative bacteria. A new β-lactamase inhibitor, avibactam, is entering the clinical arena and promising to be a major step forward in our antibiotic armamentarium. Avibactam has remarkable broad-spectrum activity in being able to inhibit classes A, C, and some class D β-lactamases. We present here structural investigations into class A β-lactamase inhibition by avibactam as we report the crystal structures of SHV-1, the chromosomal penicillinase of Klebsiella pneumoniae, and KPC-2, an acquired carbapenemase found in the same pathogen, complexed with avibactam. The 1.80 Å KPC-2 and 1.42 Å resolution SHV-1 β-lactamase avibactam complex structures reveal avibactam covalently bonded to the catalytic S70 residue. Analysis of the interactions and chair-shaped conformation of avibactam bound to the active sites of KPC-2 and SHV-1 provides structural insights into recently laboratory-generated amino acid substitutions that result in resistance to avibactam in KPC-2 and SHV-1. Furthermore, we observed several important differences in the interactions with amino acid residues, in particular that avibactam forms hydrogen bonds to S130 in KPC-2 but not in SHV-1, that can possibly explain some of the different kinetic constants of inhibition. Our observations provide a possible reason for the ability of KPC-2 β-lactamase to slowly desulfate avibactam with a potential role for the stereochemistry around the N1 atom of avibactam and/or the presence of an active site water molecule that could aid in avibactam desulfation, an unexpected consequence of novel inhibition chemistry.