Design of novel cyanovirin-N variants by modulation of binding dynamics through distal mutations.
allostery
enzyme
glycan
lectin
molecular biophysics
molecular mechanism
none
protein dynamics
structural biology
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
06 12 2022
06 12 2022
Historique:
received:
12
02
2021
accepted:
28
11
2022
entrez:
6
12
2022
pubmed:
7
12
2022
medline:
15
12
2022
Statut:
epublish
Résumé
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 β-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.
Identifiants
pubmed: 36472898
doi: 10.7554/eLife.67474
pii: 67474
pmc: PMC9725752
doi:
pii:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NCI NIH HHS
ID : R21 CA120732
Pays : United States
Informations de copyright
© 2022, Kazan, Sharma, Rahman et al.
Déclaration de conflit d'intérêts
IK, PS, MR, AB, RF, GG, SO No competing interests declared
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