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Allosteric inhibition explained through conformational ensembles sampling distinct "mixed" states.

Abstract：

:Allosteric modulation provides an effective avenue for selective and potent enzyme inhibition. Here, we summarize and critically discuss recent advances on the mechanisms of allosteric partial agonists for three representative signalling enzymes activated by cyclic nucleotides: the cAMP-dependent protein kinase (PKA), the cGMP-dependent protein kinase (PKG), and the exchange protein activated by cAMP (EPAC). The comparative analysis of partial agonism in PKA, PKG and EPAC reveals a common emerging theme, i.e. the sampling of distinct "mixed" conformational states, either within a single domain or between distinct domains. Here, we show how such "mixed" states play a crucial role in explaining the observed functional response, i.e. partial agonism and allosteric pluripotency, as well as in maximizing inhibition while minimizing potency losses. In addition, by combining Nuclear Magnetic Resonance (NMR), Molecular Dynamics (MD) simulations and Ensemble Allosteric Modeling (EAM), we also show how to map the free-energy landscape of conformational ensembles containing "mixed" states. By discussing selected case studies, we illustrate how MD simulations and EAM complement NMR to quantitatively relate protein dynamics to function. The resulting NMR- and MD-based EAMs are anticipated to inform not only the design of new generations of highly selective allosteric inhibitors, but also the choice of multidrug combinations.

journal_name

Comput Struct Biotechnol J

journal_title

Computational and structural biotechnology journal

authors

Byun JA,VanSchouwen B,Akimoto M,Melacini G

doi

10.1016/j.csbj.2020.10.026

subject

Has Abstract

pub_date

2020-11-11 00:00:00

pages

3803-3818

issn

2001-0370

pii

S2001-0370(20)30448-7

journal_volume

18

pub_type

杂志文章,评审

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