G Protein-Coupled Receptors

G protein-coupled receptors (GPCRs) constitute the largest integral membrane protein family in the human genome, with almost 1000 members. GPCRs are major contributors to the information flow into cells and, as such, are associated with a multitude of diseases that make members of this family important pharmacological targets. GPCRs have been grouped into five classes on the basis of sequence conservation, with class A being the largest and most studied.

We have solved the crystal structures of the human β2-adrenergic receptor bound to the partial inverse agonist carazolol and timolol at 2.4 Å and 2.8 Å resolution, respectively. More recently, we determined the structure of the human adenosine A2A receptor bound to the antagonists ZM281345 at 2.6 Å resolution and conducted a community wide assessment of the current status of GPCR modeling and docking. The structures provide a high-resolution view of a human G protein-coupled receptor bound to diffusible ligands. Ligand-binding site accessibility is enabled by the extracellular loops which are held out of the binding cavity by a set of disulfide bridges and unique structural motifs. An exciting discovery is the role of cholesterol in receptor stability and potential function. As a complement to the crystallographic studies, we are using hydrogen-deuterium exchange to study the dynamics of the receptor in response to different ligands.

The current research program is focused on understanding structural diversity among members of GPCR family, as well as mechanisms of signal transduction and coupling GPCRs with their partners including G proteins, GRKs, arrestins, etc.

The JCIMPT-Complexes RMI center is a technology development program focused to create new tools so that eventually we can develop a better understanding of kinetics, dynamics, and structures of membrane proteins in complex with intracellular soluble protein partners. Protein-protein interactions/ complexes is a very challenging area in need of key technological advancements.

The CMPD PSI: Biology proposal is a production center that will use structural genomics approaches to obtain representative GPCR family member structures using X-ray crystallography for the initial structure, NMR for dynamics, and co-crystallization with different ligands to understand receptor binding properties and to map out the binding sites. CMPD includes both structure and function components and is very biology focused.