Crystal structure of the human beta2 adrenergic G-protein-coupled receptor
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Crystal structure of the human beta2 adrenergic G-protein-coupled receptor. / Rasmussen, Søren Gøgsig Faarup; Choi, Hee-Jung; Rosenbaum, Daniel M; Kobilka, Tong Sun; Thian, Foon Sun; Edwards, Patricia C; Burghammer, Manfred; Ratnala, Venkata R P; Sanishvili, Ruslan; Fischetti, Robert F; Schertler, Gebhard F X; Weis, William I; Kobilka, Brian K.
In: Nature, Vol. 450, No. 7168, 15.11.2007, p. 383-7.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Crystal structure of the human beta2 adrenergic G-protein-coupled receptor
AU - Rasmussen, Søren Gøgsig Faarup
AU - Choi, Hee-Jung
AU - Rosenbaum, Daniel M
AU - Kobilka, Tong Sun
AU - Thian, Foon Sun
AU - Edwards, Patricia C
AU - Burghammer, Manfred
AU - Ratnala, Venkata R P
AU - Sanishvili, Ruslan
AU - Fischetti, Robert F
AU - Schertler, Gebhard F X
AU - Weis, William I
AU - Kobilka, Brian K
PY - 2007/11/15
Y1 - 2007/11/15
N2 - 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.
AB - 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.
KW - Adrenergic beta-2 Receptor Antagonists
KW - Animals
KW - Cell Line
KW - Crystallization
KW - Crystallography, X-Ray
KW - Drug Inverse Agonism
KW - Humans
KW - Immunoglobulin Fab Fragments
KW - Leucine
KW - Lipids
KW - Models, Molecular
KW - Protein Conformation
KW - Receptors, Adrenergic, beta-2
KW - Rhodopsin
KW - Spodoptera
U2 - 10.1038/nature06325
DO - 10.1038/nature06325
M3 - Journal article
C2 - 17952055
VL - 450
SP - 383
EP - 387
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7168
ER -
ID: 120588937