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dc.contributor.author채필석-
dc.date.accessioned2018-02-06T05:51:59Z-
dc.date.available2018-02-06T05:51:59Z-
dc.date.issued2011-01-
dc.identifier.citationNATURE 권: 469 호: 7329 페이지: 236-240en_US
dc.identifier.issn0028-0836-
dc.identifier.urihttps://www.nature.com/articles/nature09665-
dc.description.abstractG-protein-coupled receptors (GPCRs) are eukaryotic integral membrane proteins that modulate biological function by initiating cellular signalling in response to chemically diverse agonists. Despite recent progress in the structural biology of GPCRs(1), the molecular basis for agonist binding and allosteric modulation of these proteins is poorly understood. Structural knowledge of agonist-bound states is essential for deciphering the mechanism of receptor activation, and for structure-guided design and optimization of ligands. However, the crystallization of agonist-bound GPCRs has been hampered by modest affinities and rapid off-rates of available agonists. Using the inactive structure of the human beta(2) adrenergic receptor (beta(2)AR) as a guide, we designed a beta(2)AR agonist that can be covalently tethered to a specific site on the receptor through a disulphide bond. The covalent beta(2)AR-agonist complex forms efficiently, and is capable of activating a heterotrimeric G protein. We crystallized a covalent agonist-bound beta(2)AR-T4L fusion protein in lipid bilayers through the use of the lipidic mesophase method(2), and determined its structure at 3.5 angstrom resolution. A comparison to the inactive structure and an antibody-stabilized active structure (companion paper(3)) shows how binding events at both the extracellular and intracellular surfaces are required to stabilize an active conformation of the receptor. The structures are in agreement with long-timescale (up to 30 mu s) molecular dynamics simulations showing that an agonist-bound active conformation spontaneously relaxes to an inactive-like conformation in the absence of a G protein or stabilizing antibody.en_US
dc.description.sponsorshipWe acknowledge support from National Institutes of Health Grants NS028471 and GM083118 (B. K. K.), GM56169 (W. I. W.), P01 GM75913 (S. H. G), GM75915 and P50GM073210 (M. C), and P60DK-20572 (R. K. S.), the Mathers Foundation (B. K. K and W. I. W), the Lundbeck Foundation (Junior Group Leader Fellowship, S. G. F. R.), Science Foundation Ireland (07/IN.1/B1836) and FP7 COST Action CM0902 (M. C.), the Bavaria California Technology Center (P. G.), and the University of Michigan Biomedical Sciences Scholars Program(R. K. S). We thank Stefan Lober, Harald Hubner, Albert Pan and Paul Maragakis for discussion and suggestions. We thank Foon Sun Thian for help with insect cell expression.en_US
dc.language.isoenen_US
dc.publisherNATURE PUBLISHING GROUP, MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLANDen_US
dc.subjectPROTEIN-COUPLED RECEPTORen_US
dc.subjectCRYSTALLIZING MEMBRANE-PROTEINSen_US
dc.subjectMOLECULAR-DYNAMICS SIMULATIONSen_US
dc.subjectLIPIDIC MESOPHASESen_US
dc.subjectADRENERGIC-RECEPTORen_US
dc.subjectBINDING-SITEen_US
dc.subjectFORCE-FIELDSen_US
dc.subjectRHODOPSINen_US
dc.subjectACTIVATIONen_US
dc.subjectAGONISTSen_US
dc.titleStructure and function of an irreversible agonist-beta(2) adrenoceptor complexen_US
dc.typeArticleen_US
dc.relation.no7329-
dc.relation.volume469-
dc.identifier.doi10.1038/nature09665-
dc.relation.page236-240-
dc.relation.journalNATURE-
dc.contributor.googleauthorDeVree, Brian Weis-
dc.contributor.googleauthorWilliam Aragao-
dc.contributor.googleauthorDavid Gmeiner-
dc.contributor.googleauthorPeter Zhang-
dc.contributor.googleauthorCheng Rosenbaum-
dc.contributor.googleauthorDaniel M. Zhang-
dc.contributor.googleauthorCheng Rasmussen-
dc.contributor.googleauthorSoren G. F.-
dc.contributor.googleauthorChoi, Hee-Jung-
dc.contributor.googleauthorChae, Pil Seok-
dc.relation.code2011206933-
dc.sector.campusS-
dc.sector.daehakGRADUATE SCHOOL[S]-
dc.sector.departmentDEPARTMENT OF BIONANOTECHNOLOGY-
dc.identifier.pidpchae-
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GRADUATE SCHOOL[S](대학원) > BIONANOTECHNOLOGY(바이오나노학과) > Articles
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