Toho-1 β-lactamase: backbone chemical shift assignments and changes in dynamics upon binding with avibactam

Sakhrani, Varun V.; Ghosh, Rittik K.; Hilario, Eduardo; Weiss, Kevin L.; Coates, Leighton; Mueller, Leonard J.

doi:10.1007/s10858-021-00375-9

Title: Toho-1 β-lactamase: backbone chemical shift assignments and changes in dynamics upon binding with avibactam

Journal Article · Sun Jul 04 00:00:00 EDT 2021 · Journal of Biomolecular NMR

DOI:https://doi.org/10.1007/s10858-021-00375-9· OSTI ID:1958395

Sakhrani, Varun V. ^[1]; Ghosh, Rittik K. ^[1]; Hilario, Eduardo ^[1];

^[2];

^[2]

Univ. of California, Riverside, CA (United States)
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

Backbone chemical shift assignments for the Toho-1 β-lactamase (263 amino acids, 28.9 kDa) are reported based on triple resonance solution-state NMR experiments performed on a uniformly ²H,¹³C,¹⁵N-labeled sample. These assignments allow for subsequent site-specific characterization at the chemical, structural, and dynamical levels. At the chemical level, titration with the non-β-lactam β-lactamase inhibitor avibactam is found to give chemical shift perturbations indicative of tight covalent binding that allow for mapping of the inhibitor binding site. At the structural level, protein secondary structure is predicted based on the backbone chemical shifts and protein residue sequence using TALOS-N and found to agree well with structural characterization from X-ray crystallography. At the dynamical level, model-free analysis of ¹⁵N relaxation data at a single field of 16.4 T reveals well-ordered structures for the ligand-free and avibactam-bound enzymes with generalized order parameters of ~0.85. Complementary relaxation dispersion experiments indicate that there is an escalation in motions on the millisecond timescale in the vicinity of the active site upon substrate binding. The combination of high rigidity on short timescales and active site flexibility on longer timescales is consistent with hypotheses for achieving both high catalytic efficiency and broad substrate specificity: the induced active site dynamics allows variously sized substrates to be accommodated and increases the probability that the optimal conformation for catalysis will be sampled.

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Research Organization:: Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

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

Grant/Contract Number:: AC05-00OR22725; CHE1710671

OSTI ID:: 1958395

Journal Information:: Journal of Biomolecular NMR, Vol. 75, Issue 8-9; ISSN 0925-2738

Publisher:: SpringerCopyright Statement

Country of Publication:: United States

Language:: English

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37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
59 BASIC BIOLOGICAL SCIENCES
β-lactamase
protein NMR
backbone chemical shift assignments
avibactam
non-β-lactam inhibitors
15N backbone amide relaxation
protein backbone dynamics
ligand-protein binding

Title: Toho-1 β-lactamase: backbone chemical shift assignments and changes in dynamics upon binding with avibactam

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