Journal
NATURE COMMUNICATIONS
Volume 13, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-35029-3
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Funding
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272201700060C]
- U.S. Department of Energy (DOE) Office of Science
- DOE Office of Science [DEAC02-06CH11357]
- US Department of Energy, Office of Biological and Environmental Research [DE-AC02 06CH11357]
- National Institute of General Medical Sciences of the National Institutes of Health [P41 GM118217]
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Serial x-ray crystallography can reveal binding events and chemical conversions during enzymatic reactions. This study used time-resolved serial synchrotron crystallography to analyze the structure, binding, and cleavage of moxalactam antibiotic in L1 metallo-beta-lactamase from Stenotrophomonas maltophilia.
Serial x-ray crystallography can uncover binding events, and subsequent chemical conversions occurring during enzymatic reaction. Here, we reveal the structure, binding and cleavage of moxalactam antibiotic bound to L1 metallo-beta-lactamase (MBL) from Stenotrophomonas maltophilia. Using time-resolved serial synchrotron crystallography, we show the time course of beta-lactam hydrolysis and determine ten snapshots (20, 40, 60, 80, 100, 150, 300, 500, 2000 and 4000ms) at 2.20 angstrom resolution. The reaction is initiated by laser pulse releasing Zn2+ ions from a UV-labile photocage. Two metal ions bind to the active site, followed by binding of moxalactam and the intact beta-lactam ring is observed for 100ms after photolysis. Cleavage of beta-lactam is detected at 150ms and the ligand is significantly displaced. The reaction product adjusts its conformation reaching steady state at 2000 ms corresponding to the relaxed state of the enzyme. Only small changes are observed in the positions of Zn2+ ions and the active site residues. Mechanistic details captured here can be generalized to other MBLs.
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