Effect of intracellular loop 3 on intrinsic dynamics of human 2-adrenergic receptor

dc.authoridAkten, Ebru Demet/0000-0002-0358-3171
dc.authoridDoruker, Pemra/0000-0002-4824-2223
dc.authorwosidAkten, Ebru Demet/AAG-7752-2019
dc.contributor.authorOzcan, Ozer
dc.contributor.authorUyar, Arzu
dc.contributor.authorDoruker, Pemra
dc.contributor.authorAkten, Ebru Demet
dc.date.accessioned2023-10-19T15:11:34Z
dc.date.available2023-10-19T15:11:34Z
dc.date.issued2013
dc.department-temp[Ozcan, Ozer] Bogazici Univ, Computat Sci & Engn Program, Istanbul, Turkey; [Ozcan, Ozer; Uyar, Arzu; Doruker, Pemra] Bogazici Univ, Polymer Res Ctr, Istanbul, Turkey; [Uyar, Arzu; Doruker, Pemra] Bogazici Univ, Dept Chem Engn, Istanbul, Turkey; [Akten, Ebru Demet] Kadir Has Univ, Fac Nat Sci & Engn, Dept Bioinformat & Genet, TR-34083 Istanbul, Turkeyen_US
dc.description.abstractBackground: To understand the effect of the long intracellular loop 3 (ICL3) on the intrinsic dynamics of human beta(2)-adrenergic receptor, molecular dynamics (MD) simulations were performed on two different models, both of which were based on the inactive crystal structure in complex with carazolol (after removal of carazolol and T4-lysozyme). In the so-called loop model, the ICL3 region that is missing in available crystal structures was modeled as an unstructured loop of 32-residues length, whereas in the clipped model, the two open ends were covalently bonded to each other. The latter model without ICL3 was taken as a reference, which has also been commonly used in recent computational studies. Each model was embedded into POPC bilayer membrane with explicit water and subjected to a 1 mu s molecular dynamics (MD) simulation at 310 K. Results: After around 600 ns, the loop model started a transition to a very inactive conformation, which is characterized by a further movement of the intracellular half of transmembrane helix 6 (TM6) towards the receptor core, and a close packing of ICL3 underneath the membrane completely blocking the G-protein's binding site. Concurrently, the binding site at the extracellular part of the receptor expanded slightly with the Ser207-Asp113 distance increasing to 18 angstrom from 11 angstrom, which was further elaborated by docking studies. Conclusions: The essential dynamics analysis indicated a strong coupling between the extracellular and intracellular parts of the intact receptor, implicating a functional relevance for allosteric regulation. In contrast, no such transition to the very inactive state, nor any structural correlation, was observed in the clipped model without ICL3. Furthermore, elastic network analysis using different conformers for the loop model indicated a consistent picture on the specific ICL3 conformational change being driven by global modes.en_US
dc.description.sponsorshipScientific and Technological Research Council of Turkey (TUBITAK) [109 M281]; State Planning Organization of Turkey (DPT) [2009 K120520]; Kadir Has University BAP [2010-BAP-04]; Bogazici University BAP Project [5714]en_US
dc.description.sponsorshipThis work has been partially supported by The Scientific and Technological Research Council of Turkey (TUBITAK, Project # 109 M281), State Planning Organization of Turkey (DPT) (Project # 2009 K120520) and Kadir Has University BAP (Project # 2010-BAP-04). PD acknowledges partial support by Bogazici University BAP Project (No:5714).en_US
dc.identifier.citation28
dc.identifier.doi10.1186/1472-6807-13-29en_US
dc.identifier.issn1472-6807
dc.identifier.issn1472-6807
dc.identifier.pmid24206668en_US
dc.identifier.scopus2-s2.0-84887031430en_US
dc.identifier.scopusqualityN/A
dc.identifier.urihttps://doi.org/10.1186/1472-6807-13-29
dc.identifier.urihttps://hdl.handle.net/20.500.12469/5096
dc.identifier.volume13en_US
dc.identifier.wosWOS:000329232300002en_US
dc.identifier.wosqualityN/A
dc.khas20231019-WoSen_US
dc.language.isoenen_US
dc.publisherBmcen_US
dc.relation.ispartofBmc Structural Biologyen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectProtein-Coupled ReceptorEn_Us
dc.subjectBeta(2) Adrenergic-ReceptorEn_Us
dc.subjectHuman Beta-2-Adrenergic ReceptorEn_Us
dc.subjectMolecular-DynamicsEn_Us
dc.subjectCrystal-StructureEn_Us
dc.subjectBinding-SiteEn_Us
dc.subjectCytoplasmic DomainsEn_Us
dc.subjectPartial AgonistsEn_Us
dc.subjectModelEn_Us
dc.subjectActivationEn_Us
dc.subjectProtein-Coupled Receptor
dc.subjectBeta(2) Adrenergic-Receptor
dc.subjectHuman Beta-2-Adrenergic Receptor
dc.subjectMolecular-Dynamics
dc.subjectCrystal-Structure
dc.subjectICL3en_US
dc.subjectBinding-Site
dc.subjectMolecular dynamics simulationen_US
dc.subjectCytoplasmic Domains
dc.subjectTransmembrane helix 6en_US
dc.subjectPartial Agonists
dc.subjectG-protein binding siteen_US
dc.subjectModel
dc.subjectLigand dockingen_US
dc.subjectActivation
dc.subjectEssential dynamicsen_US
dc.titleEffect of intracellular loop 3 on intrinsic dynamics of human 2-adrenergic receptoren_US
dc.typeArticleen_US
dspace.entity.typePublication

Files

Original bundle

Now showing 1 - 1 of 1
Loading...
Thumbnail Image
Name:
5096.-2pdf.pdf
Size:
84.82 KB
Format:
Adobe Portable Document Format
Description:
Tam Metin / Full Text