Journal
ELIFE
Volume 11, Issue -, Pages -Publisher
eLIFE SCIENCES PUBL LTD
DOI: 10.7554/eLife.67474
Keywords
protein dynamics; allostery; lectin; glycan; enzyme; molecular mechanism; None
Categories
Funding
- Gordon and Betty Moore Foundation [1901709]
- National Science Foundation [1715591]
- National Institutes of Health [1R21CA207832-01]
- Div Of Molecular and Cellular Bioscience
- Direct For Biological Sciences [1715591] Funding Source: National Science Foundation
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We developed an ICDC approach to identify, mutate, and assess distal sites to modulate protein function through co-evolution and dynamic coupling. The approach was validated using mutational fitness data of TEM-1 beta-lactamase and applied to identify positions and mutations in cyanovirin-N (CV-N) that can modulate binding affinity. The computational and experimental analyses revealed that the identified mutants impact the dynamics of the binding pocket and compensate for the entropic cost of binding. This work provides insights into the mechanism of distal mutations in regulating protein function and offers a blueprint for optimizing function through mutagenesis.
We develop integrated co-evolution and dynamic coupling (ICDC) approach to identify, mutate, and assess distal sites to modulate function. We validate the approach first by analyzing the existing mutational fitness data of TEM-1 beta-lactamase and show that allosteric positions co-evolved and dynamically coupled with the active site significantly modulate function. We further apply ICDC approach to identify positions and their mutations that can modulate binding affinity in a lectin, cyanovirin-N (CV-N), that selectively binds to dimannose, and predict binding energies of its variants through Adaptive BP-Dock. Computational and experimental analyses reveal that binding enhancing mutants identified by ICDC impact the dynamics of the binding pocket, and show that rigidification of the binding residues compensates for the entropic cost of binding. This work suggests a mechanism by which distal mutations modulate function through dynamic allostery and provides a blueprint to identify candidates for mutagenesis in order to optimize protein function.
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