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Structure and function of an irreversible agonist-beta(2) adrenoceptor complex

Title
Structure and function of an irreversible agonist-beta(2) adrenoceptor complex
Author
채필석
Keywords
PROTEIN-COUPLED RECEPTOR; CRYSTALLIZING MEMBRANE-PROTEINS; MOLECULAR-DYNAMICS SIMULATIONS; LIPIDIC MESOPHASES; ADRENERGIC-RECEPTOR; BINDING-SITE; FORCE-FIELDS; RHODOPSIN; ACTIVATION; AGONISTS
Issue Date
2011-01
Publisher
NATURE PUBLISHING GROUP, MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
Citation
NATURE 권: 469 호: 7329 페이지: 236-240
Abstract
G-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.
URI
https://www.nature.com/articles/nature09665
ISSN
0028-0836
DOI
10.1038/nature09665
Appears in Collections:
GRADUATE SCHOOL[S](대학원) > BIONANOTECHNOLOGY(바이오나노학과) > Articles
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