Crystal structure of the human beta2 adrenergic G-protein-coupled receptor.
Structural analysis of G-protein-coupled receptors (GPCRs) for hormones and neurotransmitters has been hindered by their low natural abundance, inherent structural flexibility, and instability in detergent solutions. Here we report a structure of the human beta2 adrenoceptor (beta2AR), which was crystallized in a lipid environment when bound to an inverse agonist and in complex with a Fab that binds to the third intracellular loop. Diffraction data were obtained by high-brilliance microcrystallography and the structure determined at 3.4 A/3.7 A resolution. The cytoplasmic ends of the beta2AR transmembrane segments and the connecting loops are well resolved, whereas the extracellular regions of the beta2AR are not seen. The beta2AR structure differs from rhodopsin in having weaker interactions between the cytoplasmic ends of transmembrane (TM)3 and TM6, involving the conserved E/DRY sequences. These differences may be responsible for the relatively high basal activity and structural instability of the beta2AR, and contribute to the challenges in obtaining diffraction-quality crystals of non-rhodopsin GPCRs.
Rasmussen
Søren G F
SG
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, Palo Alto, California 94305, USA.
Choi
Hee-Jung
HJ
Rosenbaum
Daniel M
DM
Kobilka
Tong Sun
TS
Thian
Foon Sun
FS
Edwards
Patricia C
PC
Burghammer
Manfred
M
Ratnala
Venkata R P
VR
Sanishvili
Ruslan
R
Fischetti
Robert F
RF
Schertler
Gebhard F X
GF
Weis
William I
WI
Kobilka
Brian K
BK
D058672:Adrenergic beta-2 Receptor Antagonists; D000818:Animals; D002460:Cell Line; D003460:Crystallization; D018360:Crystallography, X-Ray; D054314:Drug Inverse Agonism; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000378:metabolism; D007930:Leucine / Q000378:metabolism; D008055:Lipids / Q000737:chemistry; D008958:Models, Molecular; D011487:Protein Conformation; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry* / Q000378:metabolism; D012243:Rhodopsin / Q000737:chemistry / Q000378:metabolism; D018411:Spodoptera
D058672:Adrenergic beta-2 Receptor Antagonists; D007140:Immunoglobulin Fab Fragments; D008055:Lipids; D018343:Receptors, Adrenergic, beta-2; D012243:Rhodopsin; D007930:Leucine