New Molecular Structures Challenge Conventional Concepts of Drug Action at Receptors

-- Structures of human P2Y₁ receptor bring new excitement to GPCR research

SHANGHAI, March 30, 2015 /PRNewswire/ -- A team of Chinese and US scientists has determined the atomic structure of a cell-surface receptor that plays a critical role in thrombosis formation. This research unexpectedly discloses many new structural features, which challenge the conventional concepts of drug action at G protein-coupled receptors (GPCRs) and open a new door for future drug discovery.

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In a paper published in Nature on March 30, the researchers at Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, collaborating with research groups from National Institutes of Health (NIH, U.S.), Bridge Institute at University of Southern California (U.S.) and iHuman Institute of ShanghaiTech University (China), provided a detailed map of the human P2Y₁ receptor (P2Y₁R), a GPCR, in complex with a nucleotide antagonist MRS2500 and a non-nucleotide antagonist BPTU.

"The P2Y₁R structures helped us understand how this receptor and different types of experimental drugs interact at the molecular level, and could enable further exploration to design new and safer antithrombotic drugs with reduced adverse effects," said team leader Dr. Beili Wu, Professor of SIMM.

The P2Y₁R structures revealed two completely distinct ligand-binding sites. MRS2500 recognizes a binding site within the transmembrane bundle of P2Y₁R; however, it is different in shape and location from the nucleotide-binding site in P2Y₁₂R structure that was previously determined by the same collaboration. "This finding highlights the diversity of signal recognition mechanisms in GPCRs, and is of great value to drug design for each receptor with high selectivity," said Dr. Wu.

The most surprising finding is that BPTU binds to a pocket on the outer interface of the receptor that is embedded in the cell membrane. This is the first structurally characterized selective and high affinity GPCR ligand located entirely outside of the helical bundle. This opens new opportunities to broaden the scope of future GPCR drug discovery to target novel sites outside of the conventional GPCR ligand-binding pocket, which may facilitate the development of new pharmaceuticals for treatment of many diseases.

"The new structures will allow drug designers to work more efficiently and with greater precision to build new molecules to modulate the function of this receptor and other closely related receptors, many of which have potential for treating cancer and inflammation," said coauthor Dr. Kenneth Jacobson, Senior Investigator of NIH.