Zhang Dandan, Gao Zhan-Guo, Zhang Kaihua, Kiselev Evgeny, Crane Steven, Wang Jiang, Paoletta Silvia, Yi Cuiying, Ma Limin, Zhang Wenru, Han Gye Won, Liu Hong, Cherezov Vadim, Katritch Vsevolod, Jiang Hualiang, Stevens Raymond C, Jacobson Kenneth A, Zhao Qiang, Wu Beili
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China.
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Nature. 2015 Apr 16;520(7547):317-21. doi: 10.1038/nature14287. Epub 2015 Mar 30.
In response to adenosine 5'-diphosphate, the P2Y1 receptor (P2Y1R) facilitates platelet aggregation, and thus serves as an important antithrombotic drug target. Here we report the crystal structures of the human P2Y1R in complex with a nucleotide antagonist MRS2500 at 2.7 Å resolution, and with a non-nucleotide antagonist BPTU at 2.2 Å resolution. The structures reveal two distinct ligand-binding sites, providing atomic details of P2Y1R's unique ligand-binding modes. MRS2500 recognizes a binding site within the seven transmembrane bundle of P2Y1R, which is different in shape and location from the nucleotide binding site in the previously determined structure of P2Y12R, representative of another P2YR subfamily. BPTU binds to an allosteric pocket on the external receptor interface with the lipid bilayer, making it the first structurally characterized selective G-protein-coupled receptor (GPCR) ligand located entirely outside of the helical bundle. These high-resolution insights into P2Y1R should enable discovery of new orthosteric and allosteric antithrombotic drugs with reduced adverse effects.
对5'-二磷酸腺苷作出反应时，P2Y1受体（P2Y1R）促进血小板聚集，因此是一个重要的抗血栓药物靶点。在此，我们报告了人P2Y1R与核苷酸拮抗剂MRS2500形成复合物时分辨率为2.7 Å的晶体结构，以及与非核苷酸拮抗剂BPTU形成复合物时分辨率为2.2 Å的晶体结构。这些结构揭示了两个不同的配体结合位点，提供了P2Y1R独特配体结合模式的原子细节。MRS2500识别P2Y1R七跨膜束内的一个结合位点，其形状和位置与先前确定的P2Y12R（代表另一个P2YR亚家族）结构中的核苷酸结合位点不同。BPTU与受体外部与脂质双层的界面上的一个别构口袋结合，使其成为第一个在结构上得到表征的完全位于螺旋束外部的选择性G蛋白偶联受体（GPCR）配体。这些对P2Y1R的高分辨率见解应有助于发现副作用更小的新型正构和别构抗血栓药物。
