Allosteric communication in class A β-lactamases occurs via cooperative coupling of loop dynamics

Ioannis Galdadas, Sofia Oliveira, Catherine L Tooke, James Spencer, Adrian J Mulholland, Shozeb Haider, et al.

Research output: Contribution to journalArticle (Academic Journal)peer-review

36 Citations (Scopus)
153 Downloads (Pure)


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.
Original languageEnglish
Article numbere66567
Number of pages23
Early online date23 Mar 2021
Publication statusPublished - 21 Apr 2021

Structured keywords

  • BrisSynBio
  • Bristol BioDesign Institute


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