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2015 ; 109
(6
): 1190-201
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Allosteric Dynamic Control of Binding
#MMPMID26338442
Sumbul F
; Acuner-Ozbabacan SE
; Haliloglu T
Biophys J
2015[Sep]; 109
(6
): 1190-201
PMID26338442
show ga
Proteins have a highly dynamic nature and there is a complex interrelation
between their structural dynamics and binding behavior. By assuming various
conformational ensembles, they perform both local and global fluctuations to
interact with other proteins in a dynamic infrastructure adapted to functional
motion. Here, we show that there is a significant association between allosteric
mutations, which lead to high-binding-affinity changes, and the hinge positions
of global modes, as revealed by a large-scale statistical analysis of data in the
Structural Kinetic and Energetic Database of Mutant Protein Interactions
(SKEMPI). We further examined the mechanism of allosteric dynamics by conducting
studies on human growth hormone (hGH) and pyrin domain (PYD), and the results
show how mutations at the hinge regions could allosterically affect the
binding-site dynamics or induce alternative binding modes by modifying the
ensemble of accessible conformations. The long-range dissemination of
perturbations in local chemistry or physical interactions through an impact on
global dynamics can restore the allosteric dynamics. Our findings suggest a
mechanism for the coupling of structural dynamics to the modulation of protein
interactions, which remains a critical phenomenon in understanding the effect of
mutations that lead to functional changes in proteins.
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