Journal
NATURE
Volume 450, Issue 7168, Pages 383-U4Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature06325
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Funding
- Medical Research Council [MC_U105178937] Funding Source: Medline
- MRC [MC_U105178937] Funding Source: UKRI
- Medical Research Council [MC_U105178937] Funding Source: researchfish
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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 beta 2 adrenoceptor (beta(2)AR), 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 angstrom / 3.7 angstrom resolution. The cytoplasmic ends of the beta(2)AR transmembrane segments and the connecting loops are well resolved, whereas the extracellular regions of the beta(2)AR are not seen. The beta(2)AR 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 beta(2)AR, and contribute to the challenges in obtaining diffraction-quality crystals of non-rhodopsin GPCRs.
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