Defining the nucleotide binding sites of P2Y receptors using rhodopsin-based homology modeling
Defining the nucleotide binding sites of P2Y receptors using rhodopsin-based homology modeling
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DOI：
10.1007/s10822-006-9054-2
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发表时间：
2006-08-01
影响因子：
3.5
通讯作者：
Jacobson, Kenneth A.
中科院分区：
文献类型：
--
作者：
Ivanov, Andrei A.;Costanzi, Stefano;Jacobson, Kenneth A.
正在进行的为细胞外核苷酸模拟P2 Y受体的努力，即，内源性ADP、ATP、UDP、UTP和UDP-葡萄糖，总结并与8种已知亚型相关。P2 Y受体的基于视紫红质的同源性建模得到了越来越多的定点诱变数据的支持，主要是针对P2 Y（1）受体。通过比较P2 Y受体的分子模型，可以得出结论，核苷酸结合可以发生在螺旋束的上部，核糖部分容纳在跨膜结构域（TM）3和TM 7之间。核碱基在受体的细胞外侧的方向上朝向TM 1、TM 2和TM 7。磷酸盐链朝向TM 6，在细胞外环（ELs）的方向上，并且由三个关键的阳离子残基协调。特别地，在P2 Y（1）、P2 Y（2）、P2 Y（4）和P2 Y（6）受体中，核苷酸配体具有非常相似的位置。与其他亚型相比，P2 Y（12）受体中的ADP位于受体内部更深处，P2 Y（14）受体中UDP-葡萄糖的尿苷部分位于更深处并向TM 7移动。一般来说，这些发现与提出的小分子与其他A类GPCR的结合位点一致。
Ongoing efforts to model P2Y receptors for extracellular nucleotides, i.e., endogenous ADP, ATP, UDP, UTP, and UDP-glucose, were summarized and correlated for the eight known subtypes. The rhodopsin-based homology modeling of the P2Y receptors is supported by a growing body of site-directed mutagenesis data, mainly for P2Y(1) receptors. By comparing molecular models of the P2Y receptors, it was concluded that nucleotide binding could occur in the upper part of the helical bundle, with the ribose moiety accommodated between transmembrane domain (TM) 3 and TM7. The nucleobase was oriented towards TM1, TM2, and TM7, in the direction of the extracellular side of the receptor. The phosphate chain was oriented towards TM6, in the direction of the extracellular loops (ELs), and was coordinated by three critical cationic residues. In particular, in the P2Y(1), P2Y(2), P2Y(4), and P2Y(6) receptors the nucleotide ligands had very similar positions. ADP in the P2Y(12) receptor was located deeper inside the receptor in comparison to other subtypes, and the uridine moiety of UDP-glucose in the P2Y(14) receptor was located even deeper and shifted toward TM7. In general, these findings are in agreement with the proposed binding site of small molecules to other class A GPCRs.