title: Structural Determinants of Binding the Seven-transmembrane Domain of the Glucagon-like Peptide-1 Receptor (GLP-1R).
abstract: The glucagon-like peptide-1 receptor (GLP-1R) belongs to the secretin-like (class B) family of G protein-coupled receptors. Members of the class B family are distinguished by their large extracellular domain, which works cooperatively with the canonical seven-transmembrane (7TM) helical domain to signal in response to binding of various peptide hormones. We have combined structure-based site-specific mutational studies with molecular dynamics simulations of a full-length model of GLP-1R bound to multiple peptide ligand variants. Despite the high sequence similarity between GLP-1R and its closest structural homologue, the glucagon receptor (GCGR), nearly half of the 62 stably expressed mutants affected GLP-1R in a different manner than the corresponding mutants in GCGR. The molecular dynamics simulations of wild-type and mutant GLP-1R·ligand complexes provided molecular insights into GLP-1R-specific recognition mechanisms for the N terminus of GLP-1 by residues in the 7TM pocket and explained how glucagon-mimicking GLP-1 mutants restored binding affinity for (GCGR-mimicking) GLP-1R mutants. Structural analysis of the simulations suggested that peptide ligand binding mode variations in the 7TM binding pocket are facilitated by movement of the extracellular domain relative to the 7TM bundle. These differences in binding modes may account for the pharmacological differences between GLP-1 peptide variants.
authors.affiliation: From The National Center for Drug Screening and the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guo Shou Jing Road, Shanghai 201203, China.
authors.forename: Dehua
authors.initials: D
authors.lastname: Yang
authors.affiliation: the Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: Chris
authors.initials: C
authors.lastname: de Graaf
authors.affiliation: the Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
authors.forename: Linlin
authors.initials: L
authors.lastname: Yang
authors.affiliation: the iHuman Institute, ShanghaiTech University, 99 Haike Road, Shanghai 201203, China.
authors.forename: Gaojie
authors.initials: G
authors.lastname: Song
authors.affiliation: From The National Center for Drug Screening and the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guo Shou Jing Road, Shanghai 201203, China.
authors.forename: Antao
authors.initials: A
authors.lastname: Dai
authors.affiliation: From The National Center for Drug Screening and the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guo Shou Jing Road, Shanghai 201203, China.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Cai
authors.affiliation: From The National Center for Drug Screening and the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guo Shou Jing Road, Shanghai 201203, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Feng
authors.affiliation: the Department of Protein Structure, Novo Nordisk, Novo Nordisk Park, Malov 2760, Denmark.
authors.forename: Steffen
authors.initials: S
authors.lastname: Reedtz-Runge
authors.affiliation: the GPCR Consortium, San Marcos, California 92078.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hanson
authors.affiliation: the Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
authors.forename: Huaiyu
authors.initials: H
authors.lastname: Yang
authors.affiliation: the Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.affiliation: the iHuman Institute, ShanghaiTech University, 99 Haike Road, Shanghai 201203, China, the Bridge Institute, Departments of Biological Sciences and Chemistry, University of Southern California, Los Angeles, California 90089, and.
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Stevens
authors.affiliation: From The National Center for Drug Screening and the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guo Shou Jing Road, Shanghai 201203, China, the School of Pharmacy, Fudan University, 826 Zhang Heng Road, Shanghai 201203, China mwwang@simm.ac.cn.
authors.forename: Ming-Wei
authors.initials: MW
authors.lastname: Wang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D003412:Cricetulus; D005934:Glucagon / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000067757:Glucagon-Like Peptide-1 Receptor / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D056004:Molecular Dynamics Simulation; D016297:Mutagenesis, Site-Directed; D017354:Point Mutation; D011485:Protein Binding; D017434:Protein Structure, Tertiary
chemical_list: D000067757:Glucagon-Like Peptide-1 Receptor; D052216:Glucagon-Like Peptide 1; D005934:Glucagon
keywords: G protein-coupled receptor (GPCR); glucagon; molecular dynamics; peptide interaction; site-directed mutagenesis