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2017 ; 25
(2
): 276-286
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Networks of Dynamic Allostery Regulate Enzyme Function
#MMPMID28089447
Holliday MJ
; Camilloni C
; Armstrong GS
; Vendruscolo M
; Eisenmesser EZ
Structure
2017[Feb]; 25
(2
): 276-286
PMID28089447
show ga
Many protein systems rely on coupled dynamic networks to allosterically regulate
function. However, the broad conformational space sampled by non-coherently
dynamic systems has precluded detailed analysis of their communication
mechanisms. Here, we have developed a methodology that combines the high
sensitivity afforded by nuclear magnetic resonance relaxation techniques and
single-site multiple mutations, termed RASSMM, to identify two allosterically
coupled dynamic networks within the non-coherently dynamic enzyme cyclophilin A.
Using this methodology, we discovered two key hotspot residues, Val6 and Val29,
that communicate through these networks, the mutation of which altered
active-site dynamics, modulating enzymatic turnover of multiple substrates.
Finally, we utilized molecular dynamics simulations to identify the mechanism by
which one of these hotspots is coupled to the larger dynamic networks. These
studies confirm a link between enzyme dynamics and the catalytic cycle of
cyclophilin A and demonstrate how dynamic allostery may be engineered to tune
enzyme function.
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