7MEF

CDD-1 beta-lactamase in imidazole/MPD 10 minute avibactam complex

Summary for 7MEF

• Entry DOI: 10.2210/pdb7mef/pdb
• Related: 7LNO 7LNQ 7LNR
• Descriptor: Beta-lactamase, (2S,5R)-1-formyl-5-[(sulfooxy)amino]piperidine-2-carboxamide, CARBON DIOXIDE, ... (6 entities in total)
• Functional Keywords: gram-positive, beta-lactamase, antibiotic resistance, inhibitor, avibactam, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Clostridioides difficile (Peptoclostridium difficile)
• Total number of polymer chains: 1
• Total formula weight: 29387.93

Authors

Smith, C.A.,Vakulenko, S.B. (deposition date: 2021-04-06, release date: 2022-02-16, Last modification date: 2024-11-13)

Primary citation

Stewart, N.K.,Toth, M.,Stasyuk, A.,Vakulenko, S.B.,Smith, C.A.
In Crystallo Time-Resolved Interaction of the Clostridioides difficile CDD-1 enzyme with Avibactam Provides New Insights into the Catalytic Mechanism of Class D beta-lactamases.
Acs Infect Dis., 7:1765-1776, 2021

PubMed Abstract: Class D β-lactamases have risen to notoriety due to their wide spread in bacterial pathogens, propensity to inactivate clinically important β-lactam antibiotics, and ability to withstand inhibition by the majority of classical β-lactamase inhibitors. Understanding the catalytic mechanism of these enzymes is thus vitally important for the development of novel antibiotics and inhibitors active against infections caused by antibiotic-resistant bacteria. Here we report an time-resolved study of the interaction of the class D β-lactamase CDD-1 from with the diazobicyclooctane inhibitor, avibactam. We show that the catalytic carboxylated lysine, a residue that is essential for both acylation and deacylation of β-lactams, is sequestered within an internal sealed pocket of the enzyme. Time-resolved snapshots generated in this study allowed us to observe decarboxylation of the lysine and movement of CO and water molecules through a transient channel formed between the lysine pocket and the substrate binding site facilitated by rotation of the side chain of a conserved leucine residue. These studies provide novel insights on avibactam binding to CDD-1 and into the catalytic mechanism of class D β-lactamases in general.

PubMed: 33908775
DOI: 10.1021/acsinfecdis.1c00094

Experimental method

X-RAY DIFFRACTION (1.9 Å)