Featured System - September 2014
Short description: PSI researchers have revealed a novel rearrangement in a purine-binding GPCR, opening new avenues for the design of blood clotting drugs.
G-protein-coupled receptors (GPCR) are involved in many aspects of cell communication, and thus are popular targets for many clinical drugs. PSI researchers at the GPCR network have recently reported the structure of an important GPCR target for the development of drugs to block blood clotting, the P2Y12 receptor, which is important for the aggregation of platelets. Several existing anti-clotting drugs bind to this receptor, including clopidogrel (Plavix). The PSI structures will aid in the development of new drugs with better clinical characteristics.
The P2Y12 receptor, shown here from PDB entry 4pxz, is similar to other GPCRs, with the characteristic bundle of seven alpha helices extending up and down through the membrane. There are a few interesting differences, however. For instance, the fifth helix (seen here at the center in green) is kinked at the center in other GPCRs, but is long and straight in P2Y12. Also, as described in more detail below, the effector binding site is completely buried, surrounded by loops that close around the bound ligand (shown in magenta).
To solve the structure of the P2Y12 receptor, PSI researchers continued their successful approach to the structure determination of GPCRs. An engineered form of the receptor was created by splicing cytochrome b562 into the loop between helix five and six. This small protein acts as a handle that holds the slippery receptors together in the crystal lattice. In this illustration, one molecule in the crystal lattice is shown with the receptor in red and the small cytochrome in orange. A variety of lipid-like detergents (seen here in green) are also needed to glue together the membrane-spanning portions of the receptor.
Two structures of the P2Y12 receptor, from PDB entries 4pxz and 4ntj, reveal surprisingly large motion in the effector binding site. The structure with an antagonist bound is quite open, and several of the loops surrounding the site are disordered, showing a lot of motion. When the agonist binds, however, the loops close around it, forming a tight enclosed pocket. To explore these two structures in more detail, the JSmol tab below displays an interactive JSmol.
Two structures of the P2Y12 receptor are overlapped here. The structure with an antithrombotic drug, which acts as an antagonist that blocks the action of the receptor, is quite open and several of the effector-binding loops are disordered. The structure with a modified form of ADP, which acts as an agonist that activates the receptor, is closed around the ligand. Use the buttons to compare the two structures and change the representation.
Zhang, K. et al. Structure of the human P2Y12 receptor in complex with an antithrombotic drug. Nature 509, 115-118 (2014).
Zhang, J. et al. Agonist-bound structure of the human P2Y12 receptor. Nature 509, 119-122 (2014).