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Conformational sampling, catalysis, and evolution of the bacterial phosphotriesterase
Open accessAbstract
To efficiently catalyze a chemical reaction, enzymes are required to maintain fast rates for formation of the Michaelis complex, the chemical reaction and product release. These distinct demands could be satisfied via fluctuation between different conformational substates (CSs) with unique configurations and catalytic properties. However, there is debate as to how these rapid conformational changes, or dynamics, exactly affect catalysis. As a model system, we have studied bacterial phosphotriesterase (PTE), which catalyzes the hydrolysis of the pesticide paraoxon at rates limited by a physical barrier—either substrate diffusion or conformational change. The mechanism of paraoxon hydrolysis is understood in detail and is based on a single, dominant, enzyme conformation. However, the other aspects of substrate turnover (substrate binding and product release), although possibly rate-limiting, have received relatively little attention. This work identifies “open” and “closed” CSs in PTE and dominant structural transition in the enzyme that links them. The closed state is optimally preorganized for paraoxon hydrolysis, but seems to block access to/from the active site. In contrast, the open CS enables access to the active site but is poorly organized for hydrolysis. Analysis of the structural and kinetic effects of mutations distant from the active site suggests that remote mutations affect the turnover rate by altering the conformational landscape.
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“Conformational sampling for bacterial phosphotriesterase,443 maltose binding protein,444 and choline oxidase,445 cytochrome bc1 complex,446 and many other lid-gated enzymes indicated that the closed and open conformations are in equilibrium prior to ligand binding, permitting a conformational selection pathway at different catalytic steps.447”
From Protein Ensembles: How Does Nature Harness Thermodynamic Fluctuations for Life? The Diverse Functional Roles of Conformational Ensembles in the Cell (2016) · cites this paper as [443]
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Metadata
- Authors
- Jackson, C. J., Foo, J.-L., Tokuriki, N., Afriat, L., Carr, P. D., Kim, H.-K., Schenk, G., Tawfik, D. S., & Ollis, D. L.
- Affiliations
- Institut de Biologie Structurale (FR)
- Australian National University (AU)
- University of Cambridge (GB)
- Weizmann Institute of Science, Rehovot 76100, Israel;
- The University of Queensland (AU)
- Weizmann Institute of Science (IL)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-12-22
- Volume
- 106
- Issue
- 51
- Pages
- 21631-21636
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2799856
- OpenAlex
- W2000385523
- Cited by
- 119
- References
- 45
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 9 · 2023: 5 · 2022: 7 · 2021: 2 · 2020: 4 · 2019: 8 · 2018: 5 · 2017: 8 · 2016: 11 · 2015: 12 · 2014: 7 · 2013: 9 · 2012: 7
- FWCI
- 3.62
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ANU Open Research (Australian National University) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Chemistry › Organic Chemistry › Physical Organic Chemistry and Reaction Kinetics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
- Keywords
- conformational states, enzyme catalysis, paraoxon hydrolysis, enzyme dynamics, conformational change, substrate binding, product launch, active site access, conformational landscape, enzyme evolution, pesticide hydrolysis
- MeSH terms
- Bacteria, Kinetics, Models, Molecular, Mutation, Protein Conformation, Evolution, Molecular, Phosphoric Triester Hydrolases, Biocatalysis
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