The predicted 3D structure of the human D2 dopamine receptor and the binding site and binding affinities for agonists and antagonists
The predicted 3D structure of the human D2 dopamine receptor and the binding site and binding affinities for agonists and antagonists
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DOI：
10.1073/pnas.0400100101
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发表时间：
2004-03-16
影响因子：
11.1
通讯作者：
Goddard, WA
中科院分区：
文献类型：
--
作者：
Kalani, MYS;Vaidehi, N;Goddard, WA
多巴胺神经递质及其受体在神经系统神经元信息传递的细胞信号过程中起着至关重要的作用。随着多巴胺受体的3D结构以及多巴胺和其他激动剂和拮抗剂结合位点的可用性，帕金森病和精神分裂症等疾病的改进治疗方法的发展将大大加强。我们在这里报告了人类D2多巴胺受体长异构体的3D结构，利用第一性原理理论和计算技术从初级序列预测（即，我们没有使用生物信息学或实验3D结构信息来预测结构）。通过比较预测的结合位点和D2受体中多巴胺、三种已知多巴胺激动剂（抗帕金森病）和七种已知拮抗剂（抗精神病）的相对结合亲和力来验证预测的3D结构。这些结构正确地预测了结合多巴胺和几种拮抗剂的关键残基，通过突变研究确定，并给出了与实验良好相关的相对结合亲和力。多巴胺和激动剂的预期结合位点位于跨膜（TM）螺旋3、4、5和6之间，而最佳拮抗剂与涉及TM螺旋2、3、4、6和7的位点结合，与TM螺旋5接触最少。我们确定了激动剂和拮抗剂结合位点之间的特征差异。
Dopamine neurotransmitter and its receptors play a critical role in the cell signaling process responsible for information transfer in neurons functioning in the nervous system. Development of improved therapeutics for such disorders as Parkinson's disease and schizophrenia would be significantly enhanced with the availability of the 3D structure for the dopamine receptors and of the binding site for dopamine and other agonists and antagonists. We report here the 3D structure of the long isoform of the human D2 dopamine receptor, predicted from primary sequence using first-principles theoretical and computational techniques (i.e., we did not use bioinformatic or experimental 3D structural information in predicting structures). The predicted 3D structure is validated by comparison of the predicted binding site and the relative binding affinities of dopamine, three known dopamine agonists (antiparkinsonian), and seven known antagonists (antipsychotic) in the D2 receptor to experimentally determined values. These structures correctly predict the critical residues for binding dopamine and several antagonists, identified by mutation studies, and give relative binding affinities that correlate well with experiments. The predicted binding site for dopamine and agonists is located between transmembrane (TM) helices 3,4,5, and 6, whereas the best antagonists bind to a site involving TM helices 2, 3, 4, 6, and 7 with minimal contacts to TM helix 5. We identify characteristic differences between the binding sites of agonists and antagonists.