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Allosteric inhibition of TEM-1 β lactamase: Microsecond molecular dynamics simulations provide mechanistic insights.

ABSTRACT: β-lactam antibiotics target DD-transpeptidases, enzymes that perform the last step of bacterial cell-wall synthesis. To block the antimicrobial activity of these antibiotics, bacteria have evolved lactamases that render them inert. Among these, TEM-1, a class A lactamase, has been extensively studied. In 2004, Horn et al. described a novel allosteric TEM-1 inhibitor, FTA, that binds distant from the TEM-1 orthosteric (penicillin-binding) pocket. TEM-1 has subsequently become a model for the study of allostery. In the present work, we perform molecular dynamics simulations of FTA-bound and FTA-absent TEM-1, totaling ~3 μS, that provide new insight into TEM-1 inhibition. In one of the simulations, bound FTA assumed a conformation different than that observed crystallographically. We provide evidence that the alternate pose is physiologically plausible and describe how it impacts our understanding of TEM-1 allostery.

SUBMITTER: Hellemann E

PROVIDER: S-EPMC10044111 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Allosteric inhibition of TEM-1 β lactamase: Microsecond molecular dynamics simulations provide mechanistic insights.

Hellemann Erich E Nallathambi Amrita A Durrant Jacob D JD

Protein science : a publication of the Protein Society 20230401 4

β-lactam antibiotics target DD-transpeptidases, enzymes that perform the last step of bacterial cell-wall synthesis. To block the antimicrobial activity of these antibiotics, bacteria have evolved lactamases that render them inert. Among these, TEM-1, a class A lactamase, has been extensively studied. In 2004, Horn et al. described a novel allosteric TEM-1 inhibitor, FTA, that binds distant from the TEM-1 orthosteric (penicillin-binding) pocket. TEM-1 has subsequently become a model for the stud ...[more]

PMID: 36906819

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Allosteric inhibition of TEM-1 β lactamase: Microsecond molecular dynamics simulations provide mechanistic insights.

Publications

Allosteric inhibition of TEM-1 β lactamase: Microsecond molecular dynamics simulations provide mechanistic insights.

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