Group B GPCR Modeling

Scientists at MolSoft in collaboration with Dr. Larry Miller's group at the Mayo Clinic and Dr. Patrick Sexton at Monash University Melbourne have been successful at modeling the peptide-receptor interaction for secretin. Secretin is an important drug target and currently no atomic resolution information is available for Family B GPCRs. The secretin models were based upon extensive cross-linking, FRET distances, mutagenesis, and structure activity relationship data. The peptide docking and modeling was performed using ICM-Pro.

References.

Dong M, Lam PC, Pinon DI, Orry A, Sexton PM, Abagyan R, Miller LJ. Secretin occupies a single protomer of the homo-dimeric secretin receptor complex. Insights from photoaffinity labeling studies using dual sites of covalent attachment. J Biol Chem. 2010 Mar 26;285(13):9919-31.

Dong M, Lam PC, Pinon DI, Abagyan R, Miller LJ. Elucidation of the molecular basis of cholecystokinin Peptide docking to its receptor using site-specific intrinsic photoaffinity labeling and molecular modeling. Biochemistry 2009 Jun;48(23):5303-5312.

Gao F, Harikumar KG, Dong M, Lam PC, Sexton PM, Christopoulos A, Bordner A, Abagyan R, Miller LJ. Functional importance of a structurally distinct homodimeric complex of the family B G protein-coupled secretin receptor. Mol. Pharmacol 2009 Aug;76(2):264-274.

Dong M, Lam PC, Pinon DI, Sexton PM, Abagyan R, Miller LJ. Spatial approximation between secretin residue five and the third extracellular loop of its receptor provides new insight into the molecular basis of natural agonist binding. Mol. Pharmacol 2008 Aug;74(2):413-422.

Harikumar KG, Lam PC, Dong M, Sexton PM, Abagyan R, Miller LJ. Fluorescence resonance energy transfer analysis of secretin docking to its receptor: mapping distances between residues distributed throughout the ligand pharmacophore and distinct receptor residues. J Biol Chem. 2007 Nov 9;282(45):32834-43.

Dong M, Lam PC, Gao F, Hosohata K, Pinon DI, Sexton PM, Abagyan R, Miller LJ. Molecular approximations between residues 21 and 23 of secretin and its receptor: development of a model for peptide docking with the amino terminus of the secretin receptor. Mol Pharmacol. 2007 Aug;72(2):280-90.