High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor.
Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors constitute the largest family of eukaryotic signal transduction proteins that communicate across the membrane. We report the crystal structure of a human beta2-adrenergic receptor-T4 lysozyme fusion protein bound to the partial inverse agonist carazolol at 2.4 angstrom resolution. The structure provides a high-resolution view of a human G protein-coupled receptor bound to a diffusible ligand. Ligand-binding site accessibility is enabled by the second extracellular loop, which is held out of the binding cavity by a pair of closely spaced disulfide bridges and a short helical segment within the loop. Cholesterol, a necessary component for crystallization, mediates an intriguing parallel association of receptor molecules in the crystal lattice. Although the location of carazolol in the beta2-adrenergic receptor is very similar to that of retinal in rhodopsin, structural differences in the ligand-binding site and other regions highlight the challenges in using rhodopsin as a template model for this large receptor family.
Cherezov
Vadim
V
Department of Molecular Biology, Scripps Research Institute, La Jolla, CA 92037, USA.
Rosenbaum
Daniel M
DM
Hanson
Michael A
MA
Rasmussen
Søren G F
SG
Thian
Foon Sun
FS
Kobilka
Tong Sun
TS
Choi
Hee-Jung
HJ
Kuhn
Peter
P
Weis
William I
WI
Kobilka
Brian K
BK
Stevens
Raymond C
RC
D017122:Bacteriophage T4 / Q000201:enzymology; D001665:Binding Sites; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism; D003460:Crystallization; D018360:Crystallography, X-Ray; D054314:Drug Inverse Agonism; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D009113:Muramidase / Q000737:chemistry / Q000378:metabolism; D011412:Propanolamines / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D012243:Rhodopsin / Q000737:chemistry / Q000378:metabolism; D055672:Static Electricity
D008024:Ligands; D011412:Propanolamines; D018343:Receptors, Adrenergic, beta-2; D011993:Recombinant Fusion Proteins; C014382:carazolol; D012243:Rhodopsin; D002784:Cholesterol; D009113:Muramidase