GPCRs as Structural Targets at the ATCG3D
· Over 1,000 G protein-coupled receptors (GPCRs) are expressed in the human genome.
· These transmembrane signal transduction proteins mediate a majority of cell-cell communication in humans and other vertebrates.
· Specifically, GPCRs are responsible for the initiation (and in some cases regulation) of a vast range of cellular processes including neurotransmission and homeostasis.
· Ligand binding to the cell surface-exposed region of the GPCR followed by conformational activation of the associated cytoplasmic G-protein constitutes the mechanism of signal transduction.
· Stimulatory ligands and activators include macromolecules, hormones, neurotransmitters, odorants, and light. GPCRs with unidentified stimulatory ligands are labeled orphan GPCRs.
· G-protein and receptor identities are defined by the G-protein alpha-subunit because it is the unique region that interacts with the GPCR and various effector components inside the cell.
· GPCRs constitute roughly half of all modern pharmaceutical drug targets.
· Despite their ubiquity, only four GPCR structures have been solved to date, bovine rhodopsin, turkey beta-1-adrenergic receptor, human beta-2-adrenergic receptor, and human adenosine A2A.
· GPCRs are difficult targets for crystallographic characterization, due to their water-insoluble transmembrane domains, large size, and poor stability.
· Ongoing robotic screening and LCP crystallization techniques are successfully employed in the crystallographic characterization of target GPCRs.
· Agonist, antagonist, and inverse agonists are functionally studied in complex with their associated GPCRs, both structurally and biochemically.
· The ATCG3D structure production program is exclusively focused on the high-resolution structure determination of human GPCRs and their complexes.
· Technologies developed through this work provide improved tools for macromolecular crystallography that reduce the time and resources required for membrane protein structure determination.
· Results from our studies of GPCRs and the associated complexes provide fundamental knowledge in the areas of cell biology, biochemistry, and human health.