@article{e036594472454f8e991e8af497a40d6f,
title = "Structure of the human glucagon class B G-protein-coupled receptor",
abstract = "Binding of the glucagon peptide to the glucagon receptor (GCGR) triggers the release of glucose from the liver during fasting; thus GCGR plays an important role in glucose homeostasis. Here we report the crystal structure of the seven transmembrane helical domain of human GCGR at 3.4 {\AA} resolution, complemented by extensive site-specific mutagenesis, and a hybrid model of glucagon bound to GCGR to understand the molecular recognition of the receptor for its native ligand. Beyond the shared seven transmembrane fold, the GCGR transmembrane domain deviates from class A G-protein-coupled receptors with a large ligand-binding pocket and the first transmembrane helix having a 'stalk' region that extends three alpha-helical turns above the plane of the membrane. The stalk positions the extracellular domain (∼12 kilodaltons) relative to the membrane to form the glucagon-binding site that captures the peptide and facilitates the insertion of glucagon's amino terminus into the seven transmembrane domain.",
author = "Siu, {Fai Yiu} and Min He and {De Graaf}, Chris and Han, {Gye Won} and Dehua Yang and Zhiyun Zhang and Caihong Zhou and Qingping Xu and Daniel Wacker and Joseph, {Jeremiah S.} and Wei Liu and Jesper Lau and Vadim Cherezov and Vsevolod Katritch and Wang, {Ming Wei} and Stevens, {Raymond C.}",
note = "Funding Information: Acknowledgements This work was supported by NIH Roadmap grant P50 GM073197 for technology development (V.C. and R.C.S.), and PSI:Biology grant U54 GM094618 for biological studies and structure production (target GPCR-49) (V.K., V.C. and R.C.S.); PSI:Biology grant U54 GM094586 for structure QC; The Ministry of Health grants 2012ZX09304-011 and 2013ZX09507002 (M.-W.W.), Shanghai Science and Technology Development Fund 11DZ2292200 (M.-W.W.); Novo Nordisk-Chinese Academy of Sciences Research Fund NNCAS-2011-7 (M.-W.W.); Thousand Talents Program in China (R.C.S. and M.-W.W.); NIH Postdoctoral Training Grant (NRSA) F32 DK088392 (F.Y.S.); The Netherlands Organization for Scientific Research (NWO) through a VENI grant (Grant 700.59.408 to C.d.G.); COST Action CM1207, GLISTEN (C.d.G). We also thank V. Hruby and M. Cai for advice with the glucagon binding assay and general discussions; J. Velasquez for help with molecular biology; T. Trinh and M. Chu for help with baculovirus expression; K. Kadyshevskaya for assistance with figure preparation; X. Q. Cai, J. Wang, Y. Feng, A. T. Dai, Y. Zhou, J. J. Deng, Y. B. Dai and J. W. Zhao for technical assistance in mutation studies; A. Walker for assistance with manuscript preparation; and J. Smith and R. Fischetti for assistance in development and use of the minibeam and beamtime at GM/CA-CAT beamline 23-ID at the Advanced Photon Source, which is supported by National Cancer Institute grant Y1-CO-1020 and National Institute of General Medical Sciences grant Y1-GM-1104.",
year = "2013",
doi = "10.1038/nature12393",
language = "English (US)",
volume = "499",
pages = "444--449",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7459",
}