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 Å 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.
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Fai Yiu
authors.initials: FY
authors.lastname: Siu
authors.forename: Min
authors.initials: M
authors.lastname: He
authors.forename: Chris
authors.initials: C
authors.lastname: de Graaf
authors.forename: Gye Won
authors.initials: GW
authors.lastname: Han
authors.forename: Dehua
authors.initials: D
authors.lastname: Yang
authors.forename: Zhiyun
authors.initials: Z
authors.lastname: Zhang
authors.forename: Caihong
authors.initials: C
authors.lastname: Zhou
authors.forename: Qingping
authors.initials: Q
authors.lastname: Xu
authors.forename: Daniel
authors.initials: D
authors.lastname: Wacker
authors.forename: Jeremiah S
authors.initials: JS
authors.lastname: Joseph
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Jesper
authors.initials: J
authors.lastname: Lau
authors.forename: Vadim
authors.initials: V
authors.lastname: Cherezov
authors.forename: Vsevolod
authors.initials: V
authors.lastname: Katritch
authors.forename: Ming-Wei
authors.initials: MW
authors.lastname: Wang
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Stevens
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D002462:Cell Membrane / Q000378:metabolism; D018360:Crystallography, X-Ray; D005934:Glucagon / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D019718:Receptors, CXCR4 / Q000737:chemistry / Q000145:classification; D018027:Receptors, Glucagon / Q000737:chemistry* / Q000145:classification* / Q000235:genetics / Q000378:metabolism
chemical_list: D008024:Ligands; D019718:Receptors, CXCR4; D018027:Receptors, Glucagon; D005934:Glucagon