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Crystal structure of chimeric beta-lactamase cTEM-19m at 1.2 angstrom resolutionCrystal structure of chimeric beta-lactamase cTEM-19m at 1.2 angstrom resolution
Structural highlights
FunctionBLAT_ECOLX TEM-type are the most prevalent beta-lactamases in enterobacteria; they hydrolyze the beta-lactam bond in susceptible beta-lactam antibiotics, thus conferring resistance to penicillins and cephalosporins. TEM-3 and TEM-4 are capable of hydrolyzing cefotaxime and ceftazidime. TEM-5 is capable of hydrolyzing ceftazidime. TEM-6 is capable of hydrolyzing ceftazidime and aztreonam. TEM-8/CAZ-2, TEM-16/CAZ-7 and TEM-24/CAZ-6 are markedly active against ceftazidime. IRT-4 shows resistance to beta-lactamase inhibitors.BLP4_PSEAI Hydrolyzes both carbenicillin and oxacillin. Publication Abstract from PubMedUnderstanding the principles of protein dynamics will help guide engineering of protein function: altering protein motions may be a barrier to success or may be an enabling tool for protein engineering. The impact of dynamics on protein function is typically reported over a fraction of the full scope of motional timescales. If motional patterns vary significantly at different timescales, then only by monitoring motions broadly will we understand the impact of protein dynamics on engineering functional proteins. Using an integrative approach combining experimental and in silico methodologies, we elucidate protein dynamics over the entire span of fast to slow timescales (ps to ms) for a laboratory-engineered system composed of five interrelated beta-lactamases: two natural homologs and three laboratory-recombined variants. Fast (ps-ns) and intermediate (ns-micros) dynamics were mostly conserved. However, slow motions (micros-ms) were few and conserved in the natural homologs yet were numerous and widely dispersed in their recombinants. Nonetheless, modified slow dynamics were functionally tolerated. Crystallographic B-factors from high-resolution X-ray structures were partly predictive of the conserved motions but not of the new slow motions captured in our solution studies. Our inspection of protein dynamics over a continuous range of timescales vividly illustrates the complexity of dynamic impacts of protein engineering as well as the functional tolerance of an engineered enzyme system to new slow motions. The Structural Dynamics of Engineered beta-Lactamases Vary Broadly on Three Timescales yet Sustain Native Function.,Gobeil SMC, Ebert MCCJC, Park J, Gagne D, Doucet N, Berghuis AM, Pleiss J, Pelletier JN Sci Rep. 2019 Apr 30;9(1):6656. doi: 10.1038/s41598-019-42866-8. PMID:31040324[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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