Allosteric Communication in Class A β-lactamases Occurs Via Cooperative Coupling of Loop Dynamics

Overview

Journal Elife

Specialty Biology

Date 2021 Mar 23

PMID 33755013

Citations 36

Authors

Ioannis Galdadas

Shen Qu

Ana Sofia F Oliveira

Edgar Olehnovics

Andrew R Mack

Maria F Mojica

Pratul K Agarwal

Catherine L Tooke

Francesco Luigi Gervasio

James Spencer

Robert A Bonomo

Adrian J Mulholland

Shozeb Haider

Affiliations

Soon will be listed here.

Abstract

Understanding allostery in enzymes and tools to identify it offer promising alternative strategies to inhibitor development. Through a combination of equilibrium and nonequilibrium molecular dynamics simulations, we identify allosteric effects and communication pathways in two prototypical class A β-lactamases, TEM-1 and KPC-2, which are important determinants of antibiotic resistance. The nonequilibrium simulations reveal pathways of communication operating over distances of 30 Å or more. Propagation of the signal occurs through cooperative coupling of loop dynamics. Notably, 50% or more of clinically relevant amino acid substitutions map onto the identified signal transduction pathways. This suggests that clinically important variation may affect, or be driven by, differences in allosteric behavior, providing a mechanism by which amino acid substitutions may affect the relationship between spectrum of activity, catalytic turnover, and potential allosteric behavior in this clinically important enzyme family. Simulations of the type presented here will help in identifying and analyzing such differences.

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