title: Predicted structure of agonist-bound glucagon-like peptide 1 receptor, a class B G protein-coupled receptor.
abstract: The glucagon-like peptide 1 receptor (GLP1R) is a G protein-coupled receptor (GPCR) involved in insulin synthesis and regulation; therefore, it is an important drug target for treatment of diabetes. However, GLP1R is a member of the class B1 family of GPCRs for which there are no experimental structures. To provide a structural basis for drug design and to probe class B GPCR activation, we predicted the transmembrane (TM) bundle structure of GLP1R bound to the peptide Exendin-4 (Exe4; a GLP1R agonist on the market for treating diabetes) using the MembStruk method for scanning TM bundle conformations. We used protein-protein docking methods to combine the TM bundle with the X-ray crystal structure of the 143-aa N terminus coupled to the Exe4 peptide. This complex was subjected to 28 ns of full-solvent, full-lipid molecular dynamics. We find 14 strong polar interactions of Exe4 with GLP1R, of which 8 interactions are in the TM bundle (2 interactions confirmed by mutation studies) and 6 interactions involve the N terminus (3 interactions found in the crystal structure). We also find 10 important hydrophobic interactions, of which 4 interactions are in the TM bundle (2 interactions confirmed by mutation studies) and 6 interactions are in the N terminus (6 interactions present in the crystal structure). Thus, our predicted structure agrees with available mutagenesis studies. We suggest a number of mutation experiments to further validate our predicted structure. The structure should be useful for guiding drug design and can provide a structural basis for understanding ligand binding and receptor activation of GLP1R and other class B1 GPCRs.
authors.affiliation: Materials and Process Simulation Center 139-74, California Institute of Technology, Pasadena, CA 91125, USA. abrol@wag.caltech.edu
authors.forename: Andrea
authors.initials: A
authors.lastname: Kirkpatrick
authors.forename: Jiyoung
authors.initials: J
authors.lastname: Heo
authors.forename: Ravinder
authors.initials: R
authors.lastname: Abrol
authors.forename: William A
authors.initials: WA
authors.lastname: Goddard
mesh_terms: D015195:Drug Design; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D010455:Peptides / Q000378:metabolism*; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D018027:Receptors, Glucagon / Q000819:agonists* / Q000737:chemistry*; D014688:Venoms / Q000378:metabolism*
chemical_list: D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D000077270:Exenatide