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Predicting the agonist-bound structures of the glucagon-like peptide 1 receptor, a class B G protein-coupled receptor

Kirkpatrick, Andrea and Heo, Jiyoung and Abrol, Ravinder and Goddard, William A. (2012) Predicting the agonist-bound structures of the glucagon-like peptide 1 receptor, a class B G protein-coupled receptor. In: 244th ACS National Meeting & Exposition, August 19-23, 2012, Philadelphia, PA. http://resolver.caltech.edu/CaltechAUTHORS:20120822-095339871

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Abstract

The glucagon-like peptide 1 receptor (GLP1R) is a G protein-coupled receptor involved in insulin synthesis and regulation. It is a member of the Class B (secretin-like) family of GPCRs. Its endogenous ligand GLP1 is a peptide ligand which interacts with both the ectodomain and the transmembrane (TM) region. In the absence of crystal structures which include the TM region, the activation mechanism of this receptor is mainly speculative. In this work, we predict the structure of GLP1R bound to two peptides: GLP1 and a homologous ligand Exendin-4 (Exe4). The receptor structure was created by starting with a homol. model based on a previously predicted prostaglandin receptor structure, which underwent a detailed monte carlo sampling of TM bundle conformations. The N-terminus of Exe4 was docked into the receptor TM region, its C-terminal interactions were taken from the crystal structure of the ectodomain with Exe4, and then Exe4 was mutated to GLP1. The two structures were optimized by full-solvent mol. dynamics in a lipid bilayer environment. The resulting structures show similar modes of interaction between the receptor and the two peptides, as expected. The structures also agree well with mutagenesis studies and also explain qual. the differences obsd. between GLP1 and Exe4. In addn., we suggest residues that can be tested exptl. to validate our model. These structures provide a structural basis for moving towards understanding ligand binding and receptor activation.


Item Type:Conference or Workshop Item (Paper)
Record Number:CaltechAUTHORS:20120822-095339871
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20120822-095339871
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:33442
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:27 Aug 2012 22:52
Last Modified:27 Aug 2012 22:52

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