Reconciling the lock‐and‐key and dynamic views of canonical serine protease inhibitor action
Open accessAbstract
The efficiency of canonical serine protease inhibitors is conventionally attributed to the rigidity of their protease binding loop with no conformational change upon enzyme binding, yielding an example of the lock‐and‐key model for biomolecular interactions. However, solution‐state structural studies revealed considerable flexibility in their protease binding loop. We resolve this apparent contradiction by showing that enzyme binding of small, 35‐residue inhibitors is actually a dynamic conformer selection process on the nanosecond‐timescale. Thus, fast timescale dynamics enables the association rate to be solely diffusion‐controlled just like in the rigid‐body model.
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Serine protease, conventionally regarded as rigid lock-and-key, shows nanosecond timescale binding loop movement that selects an inhibitor conformation.
“Serine protease is conventionally regarded as fitting the rigid lock-and-key model. However, nanosecond timescale binding loop movement was observed to select an inhibitor conformation.465”
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 [465]
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- Authors
- Gáspári, Z., Várnai, P., Szappanos, B., & Perczel, A.
- Affiliations
- Eötvös Loránd University (HU)
- University of Sussex (GB)
- Corresponding author
- Gáspári, Zoltán
- Venue
- FEBS Letters
- Publisher
- Wiley
- Published
- 2009-11-20
- Volume
- 584
- Issue
- 1
- Pages
- 203-206
- ISSN
- 0014-5793 (ISSN-L)
- 1873-3468
- OpenAlex
- W1970309312
- Cited by
- 21
- References
- 29
- Citations by year
- 2024: 1 · 2022: 1 · 2021: 1 · 2020: 1 · 2018: 1 · 2017: 1 · 2016: 1 · 2015: 4 · 2014: 1 · 2013: 2 · 2012: 1
- FWCI
- 0.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- FEBS Letters (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Hungarian Scientific Research Fund (F68079, K72973, NI68466)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- serine protease inhibitors, lock-and-key model, dynamic binding, conformational selection, nanosecond dynamics, solution structure
- MeSH terms
- Trypsin Inhibitors, Molecular Dynamics Simulation, Serine Proteases
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