Thursday, April 10, 2014
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Crystal structure of purinergic
receptor P2Y G protein-coupled 12
bound to an antagonist
In vitro structural studies of P2RY12 bound to an antagonist
could aid antithrombotic drug design. P2RY12 is activated by nucleotide
binding and regulates platelet activation and thrombus formation. A 2.6 Å-resolution
crystal structure showed that antagonist-bound P2RY12 adopted a canonical
seven-transmembrane bundle of helices and that the extracellular cavity of
the receptor is divided into two pockets with the antagonist bound in one. In
silico analyses predict that both pockets could be bound by dinucleotide
or chemically related molecules. Next steps include understanding how binding
in the two pockets impacts affinity and side effects associated with P2RY12
P2RY12 antagonists marketed to treat cardiovascular disease include AstraZeneca plc
and The Medicines Co.'s
Daiichi Sankyo Co. Ltd.
and Eli Lilly and Co.'s
and Sanofi and Bristol-Myers Squibb Co.'s
At least five companies have P2RY12 antagonists in Phase III or earlier
testing to treat cardiovascular disease.
Published online April 10, 2014
status not applicable
Zhang, K. et al. Nature;
published online March 23, 2014;
Contact: Qiang Zhao, Shanghai Institute of Materia Medica,
Chinese Academy of Sciences,
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