A Three Binding Site Hypothesis for the Interaction of Ligands with Monoamine G Protein‐coupled Receptors: Implications for Combinatorial Ligand Design

E. Jacoby, J. Fauchère, E. Raimbaud, Sophie Ollivier, A. Michel, M. Spedding
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引用次数: 26

Abstract

Three-dimensional models of ligand-receptor complexes based on site-directed mutagenesis experiments of the monoamine G protein-coupled receptors reveal the existence of three distinct drug binding sites inside the receptors. Here, we develop this “three-site” hypothesis and outline its implications for the modular design of ligands for monoamine GPCRs. Molecular models of receptor-ligand complexes are built for the 5-HT1A receptor where mutagenesis studies map three spatially distinct binding regions which correspond to the binding sites of the “small, one site-filling” ligands 5-HT, propranolol and 8-OH-DPAT, respectively. The models of the 5-HT1A ligand-receptor complexes provide a frame for the discussion of other ligand-receptor interactions, including α1 and β2 adrenoceptors, D1 and D2 dopamine, and 5-HT1D and 5-HT2A receptors, where mutagenesis and modelling studies also showed occupation of the corresponding three binding locations. All three binding sites are located within the highly conserved seven helix transmembrane domain of the receptor and overlap partially at the prominent Asp residue in TM3 which constitutes the benchmark anchor site for monoamine ligands. The analysis of the sequence similarity, for each binding site, among the monoamine GPCR superfamily shows that the three loci display different degrees of evolutionary conservation. This result suggests different roles for each of the binding sites in intrinsic receptor functions and provides additional insights for the design of ligand functionality and selectivity. The existence of three distinct binding sites is also reflected by the architecture of known high affinity ligands which crosslink two or three “one site-filling” fragments around a basic amino group. Typical ligands reported in the Cipsline/MDDR portfolio illustrate this point despite the occasional difficulty of attributing the individual ligand fragments to a specific receptor site. The database exploration illustrates the binding site promiscuity of some fragments which is particularly evident for symmetrical ligands and which has implications for 3D QSAR methods dependent on alignments. We propose to generate by deconvolution of known ligands three distinct databases of site-specific bioisosters which should provide keystones for the design of novel recomposed monoamine GPCR ligands. The systematic exploration of the “three site” hypothesis should open novel perspectives for the understanding of ligand recognition for this class of therapeutically important receptors.
配体与单胺G蛋白偶联受体相互作用的三结合位点假说:对组合配体设计的影响
基于单胺G蛋白偶联受体定点诱变实验的配体-受体复合物三维模型揭示了受体内部存在三种不同的药物结合位点。在这里,我们提出了这种“三位点”假设,并概述了其对单胺gpcr配体模块化设计的影响。为5-HT1A受体建立了受体-配体复合物的分子模型,其中诱变研究绘制了三个空间上不同的结合区域,分别对应于“小的、单位点填充”配体5-HT、心得安和8-OH-DPAT的结合位点。5-HT1A配体-受体复合物的模型为讨论其他配体-受体相互作用提供了一个框架,包括α1和β2肾上腺素受体、D1和D2多巴胺、5-HT1D和5-HT2A受体,其中诱变和建模研究也显示占据了相应的三个结合位置。这三个结合位点都位于受体高度保守的7螺旋跨膜结构域内,并且部分重叠在TM3中突出的Asp残基上,这是单胺配体的基准锚位点。单胺GPCR超家族中每个结合位点的序列相似性分析表明,这三个位点表现出不同程度的进化保守性。这一结果表明了每个结合位点在内在受体功能中的不同作用,并为配体功能和选择性的设计提供了额外的见解。已知的高亲和配体的结构也反映了三个不同结合位点的存在,这些配体在一个基本氨基周围交联两个或三个“单位点填充”片段。Cipsline/MDDR组合中报道的典型配体说明了这一点,尽管有时很难将单个配体片段归因于特定的受体位点。数据库探索说明了一些片段的结合位点混杂性,这对于对称配体尤其明显,并且对依赖于比对的3D QSAR方法具有影响。我们建议通过已知配体的反褶积生成三个不同的位点特异性生物同位体数据库,这将为设计新的重组单胺GPCR配体提供基础。对“三位点”假说的系统探索将为理解这类治疗上重要受体的配体识别开辟新的视角。
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