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Published on: December 11, 2016
Allostery and population shift in drug discovery
Gozde Kar1, Ozlem Keskin, Attila Gursoy
1Center for Computational Biology and Bioinformatics and College of Engineering, Koc University Rumelifeneri Yolu, 34450 Sariyer Istanbul, Turkey.
Current Opinion in Pharmacology
|October 2, 2010
Summary
Proteins dynamically shift between conformational substates, influencing function. Allosteric events alter these populations, impacting binding sites and offering new drug discovery avenues.
Area of Science:
- Biophysics
- Structural Biology
- Biochemistry
Background:
- Proteins exist in multiple conformations, visualized by an energy landscape with valleys representing conformational substates.
- Functionally relevant protein substates are pre-existing and their populations dynamically shift due to allosteric events.
- Allosteric events induce structural perturbations, propagating energetic strain to alter substate populations and binding site characteristics.
Purpose of the Study:
- To provide an overview of dynamic conformational ensembles.
- To focus on the role of allosteric events in biological signaling.
- To propose novel strategies for drug discovery.
Main Methods:
- Review of dynamic conformational ensemble concepts.
- Analysis of allosteric event mechanisms in protein signaling.
- Integration of equilibrium fluctuation principles with genomic screening.
Main Results:
- Demonstration that allosteric events dynamically modulate protein conformational substates.
- Identification of shifts in substate populations as a key consequence of allosteric perturbations.
- Highlighting the impact of these shifts on the properties of protein binding sites.
Conclusions:
- Dynamic conformational ensembles are crucial for understanding protein allostery and signaling.
- Combining equilibrium fluctuation concepts with genomic screens presents a promising approach for drug discovery.
- Targeting allosteric mechanisms offers potential for developing novel therapeutics.
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