This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Spectacular advances in the crystallization and diffraction of G-protein coupled receptors (GPCRs) have opened an unprecedented opportunity to link structure, dynamics, and function for this pharmacologically critical family of proteins, which together comprise 40-50% of all drug targets. The specific focus of the present project is on heteromerization of the A2A adenosine receptor and the D2 domaine receptor, which have been shown to form a functional signaling unit in live striatopallidal cells, and which have been identified as a target for therapies for Parkinson's disease, drug addiction, and schizophrenia. Through a combination of very recent x-ray structures of A2A and a homology model of D2 with state-of-the-art molecular simulation, we will test existing hypotheses for the A2A-D2 dimer structure. By quantifying the effect of oligomerization on the collective motions of the dimer, we will rationalize the mechanism of allosteric and functional coupling of the receptors. GPCR oligomerization is a rapidly growing area of research, as evidence mounts for GPCR oligomers in live cells that possess emergent signaling properties. These properties include including allosteric control of ligand binding and """"""""functional selectivity,"""""""" the capacity for activation of divergent signaling pathways in a ligand-dependent manner. We also suggest a novel hypothesis regarding cofolding of a pair of unusually long intracellular domains of A2A and D2, and propose millisecond timescale folding simulations to test this hypothesis and develop suggestions for experimental validation. Finally, the data will be the first such comparison of the dynamics of A2A bound to an agonist and an antagonist, and as such are interesting for the identification of allosteric modulators of monomeric A2A. Importantly, the work leverages very recent advances in the hardware and software used for molecular dynamics simulation, which make possible microsecond timescale sampling of GPCRs in membrane environments, and millisecond timescale simulation of globular domains in aqueous environment. A close collaboration with an experimental group at the University of Delaware with expertise in A2A expression and characterization promises a tightly closed loop of synergistic simulation and experiment.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Center Core Grants (P30)
Project #
5P30RR031160-02
Application #
8364950
Study Section
Special Emphasis Panel (ZRR1-RI-2 (01))
Project Start
2011-09-01
Project End
2012-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
2
Fiscal Year
2011
Total Cost
$32,754
Indirect Cost
Name
University of Delaware
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
059007500
City
Newark
State
DE
Country
United States
Zip Code
19716
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