title: Differential Requirement of the Extracellular Domain in Activation of Class B G Protein-coupled Receptors.
abstract: G protein-coupled receptors (GPCRs) from the secretin-like (class B) family are key players in hormonal homeostasis and are important drug targets for the treatment of metabolic disorders and neuronal diseases. They consist of a large N-terminal extracellular domain (ECD) and a transmembrane domain (TMD) with the GPCR signature of seven transmembrane helices. Class B GPCRs are activated by peptide hormones with their C termini bound to the receptor ECD and their N termini bound to the TMD. It is thought that the ECD functions as an affinity trap to bind and localize the hormone to the receptor. This in turn would allow the hormone N terminus to insert into the TMD and induce conformational changes of the TMD to activate downstream signaling. In contrast to this prevailing model, we demonstrate that human class B GPCRs vary widely in their requirement of the ECD for activation. In one group, represented by corticotrophin-releasing factor receptor 1 (CRF1R), parathyroid hormone receptor (PTH1R), and pituitary adenylate cyclase activating polypeptide type 1 receptor (PAC1R), the ECD requirement for high affinity hormone binding can be bypassed by induced proximity and mass action effects, whereas in the other group, represented by glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R), the ECD is required for signaling even when the hormone is covalently linked to the TMD. Furthermore, the activation of GLP-1R by small molecules that interact with the intracellular side of the receptor is dependent on the presence of its ECD, suggesting a direct role of the ECD in GLP-1R activation.
authors.affiliation: From the Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China, VARI-SIMM Center for Structure and Function of Drug Targets and the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Li-Hua
authors.initials: LH
authors.lastname: Zhao
authors.affiliation: VARI-SIMM Center for Structure and Function of Drug Targets and the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China, Laboratory of Structural Sciences, Center for Structural Biology and Drug Discovery, Van Andel Research Institute, Grand Rapids, Michigan 49503.
authors.forename: Yanting
authors.initials: Y
authors.lastname: Yin
authors.affiliation: The National Center for Drug Screening and the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Dehua
authors.initials: D
authors.lastname: Yang
authors.affiliation: VARI-SIMM Center for Structure and Function of Drug Targets and the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
authors.affiliation: VARI-SIMM Center for Structure and Function of Drug Targets and the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Li
authors.initials: L
authors.lastname: Hou
authors.affiliation: VARI-SIMM Center for Structure and Function of Drug Targets and the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Wang
authors.affiliation: Laboratory of Structural Sciences, Center for Structural Biology and Drug Discovery, Van Andel Research Institute, Grand Rapids, Michigan 49503.
authors.forename: Kuntal
authors.initials: K
authors.lastname: Pal
authors.affiliation: VARI-SIMM Center for Structure and Function of Drug Targets and the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: The National Center for Drug Screening and the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Feng
authors.affiliation: The National Center for Drug Screening and the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Cai
authors.affiliation: The National Center for Drug Screening and the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Antao
authors.initials: A
authors.lastname: Dai
authors.affiliation: From the Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China, The Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas 77030.
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
authors.affiliation: The National Center for Drug Screening and the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Ming-Wei
authors.initials: MW
authors.lastname: Wang
authors.affiliation: Laboratory of Structural Sciences, Center for Structural Biology and Drug Discovery, Van Andel Research Institute, Grand Rapids, Michigan 49503, Karsten.Melcher@vai.org.
authors.forename: Karsten
authors.initials: K
authors.lastname: Melcher
authors.affiliation: VARI-SIMM Center for Structure and Function of Drug Targets and the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China, Laboratory of Structural Sciences, Center for Structural Biology and Drug Discovery, Van Andel Research Institute, Grand Rapids, Michigan 49503, Eric.Xu@vai.org.
authors.forename: H Eric
authors.initials: HE
authors.lastname: Xu
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D005934:Glucagon / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D000072417:Protein Domains; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000145:classification / Q000378:metabolism*; D018027:Receptors, Glucagon / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
chemical_list: C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D043562:Receptors, G-Protein-Coupled; D018027:Receptors, Glucagon; D011993:Recombinant Fusion Proteins; D052216:Glucagon-Like Peptide 1; D005934:Glucagon
keywords: G protein; G protein-coupled receptor (GPCR); glucagon; parathyroid hormone; peptide hormone