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Protein electric fields enable faster and longer-lasting covalent inhibition of beta-lactamases
Open accessPreprint — published as 10.1021/jacs.2c09876
Abstract
The widespread design of covalent drugs has focused on crafting reactive groups of proper electrophilicity and positioning towards targeted amino-acid nucleophiles. We found that environmental electric fields projected onto a reactive chemical bond, an overlooked design element, play essential roles in the covalent inhibition of TEM-1 beta-lactamase by avibactam. Using the vibrational Stark effect, the magnitudes of the electric fields that are exerted by TEM active sites onto avibactam’s reactive C=O were measured and demonstrate an electrostatic gating effect that promotes bond formation yet relatively suppresses the reverse dissociation. These results suggest new principles of covalent drug design and off-target site prediction. Unlike shape and electrostatic complementary which address binding constants, electrostatic catalysis drives reaction rates, essential for covalent inhibition, and deepens our understanding of chemical reactivity, selectivity, and stability in complex systems.
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Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764
Metadata
- Authors
- Ji, Z., Kozuch, J., Mathews, I., Diercks, C., Shamsudin, Y., Schulz, M., & Boxer, S.
- Affiliations
- Stanford University (US)
- Freie Universität Berlin (DE)
- Stanford Synchrotron Radiation Lightsource (US)
- Scripps Research Institute
- Uppsala University (SE)
- Corresponding author
- Boxer, Steven
- ORCID
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2022-09-21
- Volume
- 144
- Issue
- 45
- Pages
- 20947-20954
- ISSN
- 0002-7863 (ISSN-L)
- PMC
- PMC10066720
- OpenAlex
- W4307986581
- Cited by
- 31
- References
- 1
- Citations by year
- 2026: 6 · 2025: 8 · 2024: 9 · 2023: 7 · 2022: 1
- FWCI
- 2.05
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Journal of the American Chemical Society (publishedVersion)
- ChemRxiv (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- U.S. Department of Energy (76SF00515, DE–AC02–76SF00515, AC02‐76SF00515, No. DE-AC02–76SF00515, Contract No. DE-AC02-76SF00515, P30-GM133894, DE-AC02-)
- Australian Government
- Deutsche Forschungsgemeinschaft (KO 5464/4, DE-AC02-76SF00515)
- Knut och Alice Wallenbergs Stiftelse (DE-AC02-76SF00515)
- Freie Universität Berlin
- National Institutes of Health (DE-AC02-76SF00515)
- Office of Science (AC02-76SF00515, DE-AC02-76SF0051 5, DE-AC02, 76SF00515)
- National Institute of General Medical Sciences (GM118044, DE-AC02-76SF00515, R35GM118044, P30GM133894)
- Basic Energy Sciences (DE-AC02, 76SF00515, Contract No. DE-AC02-76SF00515, AC02-76SF00515, DE-AC-02-76SF00515)
- Biological and Environmental Research (DE- AC0276SF00515, P30GM133894)
- SLAC National Accelerator Laboratory (DEAC02−76SF00515, AC02‐76SF00515, Contract No. DE-AC02-76SF00515)
- Topics
- Health Sciences › Medicine › Microbiology (medical) › Antibiotic Resistance in Bacteria
- Physical Sciences › Chemistry › Organic Chemistry › Physical Organic Chemistry and Reaction Kinetics
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis of β-Lactam Compounds
- Keywords
- covalent drug design, beta-lactamase, TEM-1 beta-lactamase, avibactam, covalent inhibition, vibrational Stark effect, electrostatic gating, electrophilic reactivity
- MeSH terms
- beta-Lactamases, Catalytic Domain, Azabicyclo Compounds, Static Electricity, beta-Lactamase Inhibitors
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- Ji, Z., Kozuch, J., Mathews, I., Diercks, C., Shamsudin, Y., Schulz, M., & Boxer, S. (2022). Protein electric fields enable faster and longer-lasting covalent inhibition of beta-lactamases. Journal of the American Chemical Society. https://doi.org/10.26434/chemrxiv-2022-5p25j
