Maria Germana Paterlini, Principal Investigator

Studying G-protein Coupled Receptors by Using Molecular Modeling

  G-protein coupled receptors (GPCR) are membrane proteins involved in signal transduction, where the signal cascade is triggered by the binding of a large variety of ligands, from ions to hormones, to small proteins. GPCRs are characterized by a helical bundle whose structure is believed to contain a common triggering mechanism leading to activation.   Resources at the Supercomputing Institute were used to study two GPCRs: the chemokine receptor CCR5 and the lutropin/chorionotropin (LH) receptor. Models of CCR5 were constructed and examined in relation with available experimental data on the binding of chemokine-derived peptides. This study was complemented by simulations and NMR experiments of these peptides. Using the structural model of CCR5, researchers examined the binding of novel antagonist ligands using automated docking procedures. The LH receptor is a glycoprotein hormone receptor whose naturally occurring activating mutations result in gonadal dysfunction. The majority of these mutations occur in regions of the receptor undergoing conformational changes upon hormone binding. Characterization of the activating mutations therefore enhance our understand of GPCR function. Computations were used to correlate structural changes observed during the simulations with the effect of such mutations on receptor activation. Additional resources were used to generate a lipid model to be used in future simulations of membrane-bound peptides and proteins in explicit lipid systems.