Heterogeneity in M. tuberculosis β-lactamase inhibition by Sulbactam.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
07 09 2023
07 09 2023
Historique:
received:
19
12
2022
accepted:
27
08
2023
medline:
11
9
2023
pubmed:
8
9
2023
entrez:
7
9
2023
Statut:
epublish
Résumé
For decades, researchers have elucidated essential enzymatic functions on the atomic length scale by tracing atomic positions in real-time. Our work builds on possibilities unleashed by mix-and-inject serial crystallography (MISC) at X-ray free electron laser facilities. In this approach, enzymatic reactions are triggered by mixing substrate or ligand solutions with enzyme microcrystals. Here, we report in atomic detail (between 2.2 and 2.7 Å resolution) by room-temperature, time-resolved crystallography with millisecond time-resolution (with timepoints between 3 ms and 700 ms) how the Mycobacterium tuberculosis enzyme BlaC is inhibited by sulbactam (SUB). Our results reveal ligand binding heterogeneity, ligand gating, cooperativity, induced fit, and conformational selection all from the same set of MISC data, detailing how SUB approaches the catalytic clefts and binds to the enzyme noncovalently before reacting to a trans-enamine. This was made possible in part by the application of singular value decomposition to the MISC data using a program that remains functional even if unit cell parameters change up to 3 Å during the reaction.
Identifiants
pubmed: 37679343
doi: 10.1038/s41467-023-41246-1
pii: 10.1038/s41467-023-41246-1
pmc: PMC10485065
doi:
Substances chimiques
Ligands
0
Sulbactam
S4TF6I2330
beta-Lactamases
EC 3.5.2.6
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
5507Commentaires et corrections
Type : UpdateOf
Informations de copyright
© 2023. Springer Nature Limited.
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