Intrinsic Dynamics and Causality in Correlated Motions Unraveled in Two Distinct Inactive States of Human beta(2)-Adrenergic Receptor

dc.contributor.authorSöğünmez, Nuray
dc.contributor.authorAkten, Ebru Demet
dc.date.accessioned2019-06-27T08:01:10Z
dc.date.available2019-06-27T08:01:10Z
dc.date.issued2019
dc.departmentFakülteler, Mühendislik ve Doğa Bilimleri Fakültesi, Biyoinformatik ve Genetik Bölümüen_US
dc.description.abstractThe 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.en_US]
dc.identifier.citation2
dc.identifier.doi10.1021/acs.jpcb.9b01202en_US
dc.identifier.endpage3642
dc.identifier.issn1520-6106en_US
dc.identifier.issn1520-6106
dc.identifier.issue17
dc.identifier.pmid30946584en_US
dc.identifier.scopus2-s2.0-85064987918en_US
dc.identifier.scopusqualityN/A
dc.identifier.startpage3630en_US
dc.identifier.urihttps://hdl.handle.net/20.500.12469/282
dc.identifier.urihttps://doi.org/10.1021/acs.jpcb.9b01202
dc.identifier.volume123en_US
dc.identifier.wosWOS:000466989000008en_US
dc.identifier.wosqualityQ3
dc.institutionauthorAkten, Ebru Demeten_US
dc.language.isoenen_US
dc.publisherAmer Chemical Socen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/embargoedAccessen_US
dc.titleIntrinsic Dynamics and Causality in Correlated Motions Unraveled in Two Distinct Inactive States of Human beta(2)-Adrenergic Receptoren_US
dc.typeArticleen_US
dspace.entity.typePublication

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