The recent discoveries that G-protein coupled receptors(GPCRs) form homo- and hetero-oligomers, with the dimer as the minimal oligomeric arrangement, have added a new dimension of complexity to the GPCR research field. Structural and mechanistic information about GPCR dimeric/oligomeric complexes has therefore become of major importance for understanding the mechanisms of action of these complex biological systems. Current major research activities in the lab focus on developing, interpreting, and disseminating to the scientific community detailed information about the structural context of GPCR dimerization/oligomerization. They are briefly described below.

I. Identification of likely interfaces of GPCR oligomerization with computational modeling and bioinformatics tools.

Our goal is to predict the molecular determinants responsible for the oligomerization of GPCRs (both homo- and heteromers), and identify them in a structural context of receptor models, using a combined molecular modeling-bioinformatics approach. Since there is no available experimental structural data at the atomic level about GPCR dimers/oligomers, and no evidence that the homo- and hetero-oligomerization interfaces of GPCRs coincide, we developed two different computational approaches based on correlated mutation analysis that can be used to identify the most likely homo- or hetero-dimerization interfaces between the transmembrane regions of GPCRs. Inferences from these bioinformatics tools are used to construct first-generation molecular models of GPCR dimers, which in turn can serve to generate valuable hypotheses of interaction that can be tested experimentally, and help refine the proposed dimeric/oligomeric models. An important goal of these studies is to be able to suggest specific mutations that can be used to modulate dimerization/oligomerization, and thus affect receptor function in a manner that will reveal physiologically relevant mechanisms that depend and/or ensue from dimerization.

II. MD simulations of GPCR dimers/oligomers in an explicit lipid-water environment.

The correct nature and geometry of the interface(s) of GPCR homo- and heteromers is essential for understanding of the role and implications of these phenomena in the functional mechanisms of these receptors. To provide new and deeper insights into the basis of protein-protein interaction in GPCR dimers/oligomers, and the dynamic properties that may relate to their functional mechanisms, we are currently carrying out detailed MD simulations of the interfaces of activated and inactive GPCR dimers using discrete representations of the membrane and water environment. These studies will help us achieve a more complete representation of the GPCR function by identifying quantitatively the intermolecular mode of receptor activation, and adding it to current models of GPCR ligand-binding and signal transduction.

III. Construction of an Information Management System to store computational and experimental information about GPCR dimers/oligomers.

We are currently building an information management system (OKB-GPCR) to store, allow structured queries, browsing and visualization of the structural features at the interface of GPCR dimers/oligomers in a manner that will facilitate the design and interpretation of pointed physiological and pharmacological experiments.

e-mail: maf2037@med.cornell.edu

Further Information:
http://physiology.med.cornell.edu/faculty/filizola/index.html