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Cryo structure of Mycobacterium tuberculosis beta lactamase microcrystals mixed with sulbactam for 3 hoursCryo structure of Mycobacterium tuberculosis beta lactamase microcrystals mixed with sulbactam for 3 hours
Structural highlights
FunctionPublication Abstract from PubMedFor decades, researchers have been determined to elucidate essential enzymatic functions on the atomic lengths scale by tracing atomic positions in real time. Our work builds on new possibilities unleashed by mix-and-inject serial crystallography (MISC) (1-5) at X-ray free electron laser facilities. In this approach, enzymatic reactions are triggered by mixing substrate or ligand solutions with enzyme microcrystals (6) . Here, we report in atomic detail and with millisecond time-resolution how the Mycobacterium tuberculosis enzyme BlaC is inhibited by sulbactam (SUB). Our results reveal ligand binding heterogeneity, ligand gating (7-9) , cooperativity, induced fit (10,11) and conformational selection (11-13) all from the same set of MISC data, detailing how SUB approaches the catalytic clefts and binds to the enzyme non-covalently before reacting to a trans- enamine. This was made possible in part by the application of the singular value decomposition (14) to the MISC data using a newly developed program that remains functional even if unit cell parameters change during the reaction. Heterogeneity in the M. tuberculosis beta-Lactamase Inhibition by Sulbactam.,Schmidt M, Malla TN, Zielinski K, Aldama L, Bajt S, Feliz D, Hayes B, Hunter M, Kupitz C, Lisova S, Knoska J, Martin-Garcia J, Mariani V, Pandey S, Poudyal I, Sierra R, Tolstikova A, Yefanov O, Yoon CH, Ourmazd A, Fromme P, Schwander P, Barty A, Chapman H, Stojkovic E, Batyuk A, Boutet S, Phillips G, Pollack L Res Sq. 2023 Jan 10:rs.3.rs-2334665. doi: 10.21203/rs.3.rs-2334665/v1. Preprint. PMID:36712138[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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