One Receptor, Two Disparate Binding Sites

The unusual dual binding sites of the GPCR P2Y1R could lead to new blood clotting drugs.

AsianScientist (Apr. 7, 2015) – Scientists have determined the high-resolution atomic structure of a cell-surface receptor that plays a critical role in blood clot formation. This research discloses many new structural features, which challenge the conventional concepts of drug action at G protein-coupled receptors (GPCRs) and opens a new door for future drug discovery.

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

Human purinergic receptors P2Y1R and P2Y12R play a major physiological role in adenosine 5′-diphosphate (ADP)-mediated platelet aggregation, an important component of thrombosis, which can subsequently result in life-threatening diseases, such as heart attack and stroke.

While most of the available antithrombotic drugs act on P2Y12R, P2Y1R has been suggested as a new promising antithrombotic drug target and may offer a safety advantage over P2Y12R inhibitors in terms of reduced bleeding liabilities. However, efforts to develop new drugs have been impeded by poor understanding of receptor-ligand interaction.

“The P2Y1R structures help 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. Wu Beili, Professor of SIMM.

Although recognized by the same endogenous ligand ADP, P2Y1R and P2Y12R structures reveal very different features in binding their nucleotide ligands. For example, the P2Y1R structures reveal two completely distinct ligand-binding sites. The nucleotide ligand 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 previously determined by the same collaboration.

“It is amazing to observe that two GPCRs recognize the same ligand in such different ways,” said Wu. “The finding highlights the diversity of signal recognition mechanisms in GPCRs, and this is of great value to drug design for each receptor with high selectivity.”

The most surprising finding of this research is that instead of interacting within the transmembrane bundle, the non-nucleotide ligand 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 and it represents a new paradigm in ligand binding to alter signaling in GPCRs.

The P2Y1R structure 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 greatly improve drug selectivity and reduce side effects, and will thus facilitate the development of new pharmaceuticals for treatment of many severe 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 study co-author Dr. Kenneth Jacobson, Chief of the Laboratory of Bioorganic Chemistry in the National Institute of Diabetes and Digestive and Kidney Diseases at NIH.

The article can be found at: Zhang et al. (2015) Two Disparate Ligand-Binding Sites in the Human P2Y1 Receptor.

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Source: Chinese Academy of Sciences
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