Heterogeneity in M. tuberculosis β-lactamase inhibition by Sulbactam

Tek Narsingh Malla, Kara Zielinski, Luis Aldama, Sasa Bajt, Denisse Feliz, Brendon Hayes, Mark Hunter, Christopher Kupitz, Stella Lisova, Juraj Knoska, Jose Manuel Martin-Garcia, Valerio Mariani, Suraj Pandey, Ishwor Poudyal, Raymond G. Sierra, Alexandra Tolstikova, Oleksandr Yefanov, Chung Hong Yoon, Abbas Ourmazd, Petra Fromme, Peter Schwander, Anton Barty, Henry N. Chapman, Emina A. Stojkovic, Alexander Batyuk, Sébastien Boutet, George N. Phillips, Lois Pollack and Marius Schmidt ()
Additional contact information
Tek Narsingh Malla: University of Wisconsin-Milwaukee
Kara Zielinski: Cornell University
Luis Aldama: Northeastern Illinois University
Sasa Bajt: The Hamburg Centre for Ultrafast Imaging
Denisse Feliz: Northeastern Illinois University
Brendon Hayes: Linac Coherent Light Source LCLS, SLAC National Accelerator Laboratory
Mark Hunter: Linac Coherent Light Source LCLS, SLAC National Accelerator Laboratory
Christopher Kupitz: Linac Coherent Light Source LCLS, SLAC National Accelerator Laboratory
Stella Lisova: Linac Coherent Light Source LCLS, SLAC National Accelerator Laboratory
Juraj Knoska: Center for Free-Electron Laser Science CFEL, Deutsches Elektronen Synchrotron
Jose Manuel Martin-Garcia: Spanish National Research Council (CSIC)
Valerio Mariani: Linac Coherent Light Source LCLS, SLAC National Accelerator Laboratory
Suraj Pandey: University of Wisconsin-Milwaukee
Ishwor Poudyal: University of Wisconsin-Milwaukee
Raymond G. Sierra: Linac Coherent Light Source LCLS, SLAC National Accelerator Laboratory
Alexandra Tolstikova: Deutsches Elektronen-Synchrotron DESY
Oleksandr Yefanov: Center for Free-Electron Laser Science CFEL, Deutsches Elektronen Synchrotron
Chung Hong Yoon: Linac Coherent Light Source LCLS, SLAC National Accelerator Laboratory
Abbas Ourmazd: University of Wisconsin-Milwaukee
Petra Fromme: 20 Arizona State University
Peter Schwander: University of Wisconsin-Milwaukee
Anton Barty: Deutsches Elektronen-Synchrotron DESY
Henry N. Chapman: The Hamburg Centre for Ultrafast Imaging
Emina A. Stojkovic: Northeastern Illinois University
Alexander Batyuk: Linac Coherent Light Source LCLS, SLAC National Accelerator Laboratory
Sébastien Boutet: Linac Coherent Light Source LCLS, SLAC National Accelerator Laboratory
George N. Phillips: Rice University
Lois Pollack: Cornell University
Marius Schmidt: University of Wisconsin-Milwaukee

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-41246-1

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