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dc.contributor.authorÖzgür, Canan
dc.contributor.authorDoruker, Pemra
dc.contributor.authorAkten, Ebru Demet
dc.date.accessioned2019-06-27T08:01:44Z
dc.date.available2019-06-27T08:01:44Z
dc.date.issued2016
dc.identifier.issn1472-6807
dc.identifier.urihttps://hdl.handle.net/20.500.12469/455
dc.identifier.urihttps://doi.org/10.1186/s12900-016-0061-9
dc.description.abstractBackground: This study investigates the allosteric coupling that exists between the intra- and extracellular parts of human beta(2)-adrenergic receptor (beta(2)-AR) in the presence of the intracellular loop 3 (ICL3) which is missing in all crystallographic experiments and most of the simulation studies reported so far. Our recent 1 mu s long MD run has revealed a transition to the so-called very inactive state of the receptor in which ICL3 packed under the G protein's binding cavity and completely blocked its accessibility to G protein. Simultaneously an outward tilt of transmembrane helix 5 (TM5) caused an expansion of the extracellular ligand-binding site. In the current study we performed independent runs with a total duration of 4 mu s to further investigate the very inactive state with packed ICL3 and the allosteric coupling event (three unrestrained runs and five runs with bond restraints at the ligand-binding site). Results: In all three independent unrestrained runs (each 500 ns long) ICL3 preserved its initially packed/closed conformation within the studied time frame suggesting an inhibition of the receptor's activity. Specific bond restraints were later imposed between some key residues at the ligand-binding site which have been experimentally determined to interact with the ligand. Restraining the binding site region to an open state facilitated ICL3 closure whereas a relatively constrained/closed binding site hindered ICL3 packing. However the reverse operation i.e. opening of the packed ICL3 could not be realized by restraining the binding site region to a closed state. Thus any attempt failed to free the ICL3 from its locked state due to the presence of persistent hydrogen bonds. Conclusions: Overall our simulations indicated that starting with very inactive states the receptor stayed almost irreversibly inhibited which in turn decreased the overall mobility of the receptor. Bond restraints which represented the geometric restrictions caused by ligands of various sizes when bound at the ligand-binding site induced the expected conformational changes in TM5 TM6 and consequently ICL3. Still once ICL3 was packed the allosteric coupling became ineffective due to strong hydrogen bonds connecting ICL3 to the core of the receptor.
dc.language.isoEnglish
dc.publisherBMC
dc.subjectBeta(2)-Adrenergic Receptor
dc.subjectIntracellular Loop 3 (ICL3)
dc.subjectG Protein-Coupled Receptor
dc.subjectAllosteric Coupling
dc.subjectTransmembrane Helix
dc.titleInvestigation of Allosteric Coupling in Human Beta(2)-Adrenergic Receptor in the Presence of Intracellular Loop 3
dc.typeArticle
dc.relation.journalBMC Structural Biology
dc.identifier.volume16
dc.identifier.wosWOS:000379257800001
dc.identifier.doi10.1186/s12900-016-0061-9
dc.contributor.khasauthorAkten, Ebru Demet


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