Substrate Binding Induces Conformational Changes in a Class A β-lactamase That Prime It for Catalysis

Langan, Patricia S.; Vandavasi, Venu Gopal; Cooper, Sarah J.; Weiss, Kevin L.; Ginell, Stephan L.; Parks, Jerry M.; Coates, Leighton

doi:10.1021/acscatal.7b04114

Title: Substrate Binding Induces Conformational Changes in a Class A β-lactamase That Prime It for Catalysis

Journal Article · Thu Feb 15 00:00:00 EST 2018 · ACS Catalysis

DOI:https://doi.org/10.1021/acscatal.7b04114· OSTI ID:1459304

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Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Univ. of Tennessee, Knoxville, TN (United States)
Argonne National Lab. (ANL), Argonne, IL (United States); Univ. at Buffalo, Buffalo, NY (United States)
Univ. of Tennessee, Knoxville, TN (United States); Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

The emergence and dissemination of bacterial resistance to β-lactam antibiotics via β-lactamase enzymes is a serious problem in clinical settings, often leaving few treatment options for infections resulting from multidrug-resistant superbugs. Understanding the catalytic mechanism of β-lactamases is important for developing strategies to overcome resistance. Binding of a substrate in the active site of an enzyme can alter the conformations and pKas of catalytic residues, thereby contributing to enzyme catalysis. Here we report X-ray and neutron crystal structures of the class A Toho-1 β-lactamase in the apo form and an X-ray structure of a Michaelis-like complex with the cephalosporin antibiotic cefotaxime in the active site. Comparison of these structures reveals that substrate binding induces a series of changes. The side chains of conserved residues important in catalysis, Lys73 and Tyr105, and the main chain of Ser130 alter their conformations, with Nζ of Lys73 moving closer to the position of the conserved catalytic nucleophile Ser70. This movement of Lys73 closer to Ser70 is consistent with proton transfer between the two residues prior to acylation. In combination with the tightly bound catalytic water molecule located between Glu166 and the position of Ser70, the enzyme is primed for catalysis when Ser70 is activated for nucleophilic attack of the β-lactam ring. Quantum mechanical/molecular mechanical (QM/MM) free energy simulations of models of the wild-type enzyme show that proton transfer from the Nζ of Lys73 to the Oε2 atom of Glu166 is more thermodynamically favorable than when it is absent. Taken together, our findings indicate that substrate binding enhances the favorability of the initial proton transfer steps that precede the formation of the acyl-enzyme intermediate.

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Research Organization:: Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER); USDOE Office of Science (SC), Basic Energy Sciences (BES); National Science Foundation (NSF)

Grant/Contract Number:: AC05-00OR22725; AC02-06CH11357

OSTI ID:: 1459304

Alternate ID(s):: OSTI ID: 1485285

Journal Information:: ACS Catalysis, Vol. 8, Issue 3; ISSN 2155-5435

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 21 works

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