Intrinsic Dynamics and Causality in Correlated Motions Unraveled in Two Distinct Inactive States of Human Beta(2)-Adrenergic Receptor
No Thumbnail Available
Date
2019
Authors
Söğünmez, Nuray
Akten, Ebru Demet
Journal Title
Journal ISSN
Volume Title
Publisher
Amer Chemical Soc
Open Access Color
OpenAIRE Downloads
OpenAIRE Views
Abstract
The alternative inactive state of the human beta(2)-adrenergic receptor originally exposed in molecular dynamics simulations was investigated using various analysis tools to evaluate causality between correlated residue-pair fluctuations and suggest allosteric communication pathways. A major conformational shift observed in the third intracellular loop (ICL3) displayed a novel inactive state featuring an inaccessible G protein binding site blocked by ICL3 and an expanded orthosteric ligand binding site. Residue-based mean square fluctuation and stiffness calculations revealed a significant mobility decrease in ICL3 which induced a mobility increase in the remaining loop regions. This indicates conformational entropy loss in one mobile region being compensated by residual intermolecular motions in other mobile regions. Moreover the extent motions decreased and correlations that once existed between transmembrane helices shifted toward regions with increased mobility. Conditional time-delayed cross-correlation analysis identified distinct driver follower relationship profiles. Prior to its packing freely moving ICL3 was markedly driven by transmembrane helix-8 whereas once packed ICL3 controlled future fluctuations of nearby helices. Moreover two transmembrane helices (H5 and H6) started to control future fluctuations of a remote site the extracellular loop ECL2. This clearly suggests that allosteric coupling between extra- and intracellular parts intensified in agreement with the receptor's well recognized feature which is the inverse proportionality between activity and the degree of coupling.
Description
Keywords
Turkish CoHE Thesis Center URL
Fields of Science
Citation
2
WoS Q
Q3
Scopus Q
Source
Volume
123
Issue
17
Start Page
3630
End Page
3642