Allosteric Modulation of Binding Specificity by Alternative Packing of Protein Cores.

Détails

ID Serval
serval:BIB_A87AEE8073C3
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Allosteric Modulation of Binding Specificity by Alternative Packing of Protein Cores.
Périodique
Journal of molecular biology
Auteur(s)
Ben-David M., Huang H., Sun MGF, Corbi-Verge C., Petsalaki E., Liu K., Gfeller D., Garg P., Tempel W., Sochirca I., Shifman J.M., Davidson A., Min J., Kim P.M., Sidhu S.S.
ISSN
1089-8638 (Electronic)
ISSN-L
0022-2836
Statut éditorial
Publié
Date de publication
18/01/2019
Peer-reviewed
Oui
Volume
431
Numéro
2
Pages
336-350
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
Hydrophobic cores are often viewed as tightly packed and rigid, but they do show some plasticity and could thus be attractive targets for protein design. Here we explored the role of different functional pressures on the core packing and ligand recognition of the SH3 domain from human Fyn tyrosine kinase. We randomized the hydrophobic core and used phage display to select variants that bound to each of three distinct ligands. The three evolved groups showed remarkable differences in core composition, illustrating the effect of different selective pressures on the core. Changes in the core did not significantly alter protein stability, but were linked closely to changes in binding affinity and specificity. Structural analysis and molecular dynamics simulations revealed the structural basis for altered specificity. The evolved domains had significantly reduced core volumes, which in turn induced increased backbone flexibility. These motions were propagated from the core to the binding surface and induced significant conformational changes. These results show that alternative core packing and consequent allosteric modulation of binding interfaces could be used to engineer proteins with novel functions.
Mots-clé
SH3 domain, binding specificity, conformational flexibility, hydrophobic core, phage display
Pubmed
Web of science
Création de la notice
28/11/2019 13:10
Dernière modification de la notice
29/11/2019 7:26
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