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Protein Electric Fi...
Protein Electric Fields Enable Faster and Longer-Lasting Covalent Inhibition of β-Lactamases
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- Ji, Zhe (författare)
- Department of Chemistry, Stanford University, Stanford, California 94305, United States
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- Kozuch, Jacek (författare)
- Department of Physics, Experimental Molecular Biophysics, Freie Universität Berlin, Arnimallee 14, D-14195 Berlin, Germany;Research Building SupraFAB, Altensteinstreet 23a, 14195 Berlin, Germany
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- Mathews, Irimpan I. (författare)
- Stanford Synchrotron Radiation Lightsource, Menlo Park, California 94025, United States
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- Diercks, Christian S. (författare)
- Department of Chemistry, Scripps Research, La Jolla, California 92037, United States
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- Shamsudin, Yasmin (författare)
- Uppsala universitet,Institutionen för kemi - BMC
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- Schulz, Mirjam A. (författare)
- Department of Physics, Experimental Molecular Biophysics, Freie Universität Berlin, Arnimallee 14, D-14195 Berlin, Germany;Research Building SupraFAB, Altensteinstreet 23a, 14195 Berlin, Germany
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- Boxer, Steven G. (författare)
- Department of Chemistry, Stanford University, Stanford, California 94305, United States
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(creator_code:org_t)
- 2022-11-03
- 2022
- Engelska.
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 144:45, s. 20947-20954
- Relaterad länk:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- The widespread design of covalent drugs has focused on crafting reactive groups of proper electrophilicity and positioning toward 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 β-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.
Ämnesord
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Nyckelord
- Chemistry with specialization in Biophysics
- Kemi med inriktning mot biofysik
- Chemistry with specialization in Macromolecular Chemistry
- Kemi med inriktning mot makromolekylär kemi
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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