Proposed ligand binding site of the transmembrane receptor for neurotensin(8-13)
Proposed ligand binding site of the transmembrane receptor for neurotensin(8-13)
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DOI：
10.1074/jbc.271.25.15060
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发表时间：
1996-06-21
影响因子：
4.8
通讯作者：
Richelson, E
中科院分区：
文献类型：
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作者：
Pang, YP;Cusack, B;Richelson, E
我们报道了首次提出的人和大鼠神经降压素跨膜受体(8-13)的配体结合位点，相应的肽配体的结合构象，以及支持结合位点模型的定点突变研究，这些三维结构是用启发式方法结合实验数据产生的。神经降压素(8-13)结合位点主要由8个残基组成，即人受体中的Phe(326)、Ile(329)、Trp(334)、Phe(337)、Tyr(339)、Phe(341)、Tyr(342)和Tyr(344)；Phe(331)，Ile(334)，Trp(339)，Phe(342)，Phe(344)，Phe(346)，Tyr(347)和Tyr(349)位于细胞外第三环，7个芳香族残基在神经降压素受体的胞外表面形成一个芳香口袋，通过阳离子-pi，pi-pi和氢键相互作用来容纳其配体，神经降压素(8-13)配体在所提出的结合部位采用致密构象，在神经降压素(8-13)的结合构象中，Arg(9)-Pro(10)-Tyr(11)-Ile(12)的主链形成I型转角的脯氨酸，Tyr(11)的羟基与Arg(8)和Arg(9)两个胍基相互作用。这些胍基向羟基卷曲，从而它们与羟基静电相互作用，并且Arg(9)的胍基与羟基形成内氢键。所提出的三维结构不仅为神经降压素受体基因突变的合理化提供了基础，而且为了解神经降压素类似物的结合、神经降压素受体的生物学功能以及神经降压素受体的物种特异性的结构元素提供了洞察力，并可能加速开发用于神经精神疾病潜在治疗的非肽类神经降压素类似物。
We report here the first proposed ligand binding site of the transmembrane receptor for neurotensin (8-13) in human and rat, the corresponding bound conformation of the peptide ligand, and site directed mutagenesis studies that support the binding site model, These three-dimensional structures were generated by using a heuristic approach in conjunction with experimental data. The proposed neurotensin(8-13) binding site is primarily composed of eight residues (i.e., Phe(326), Ile(329), Trp(334), Phe(337), Tyr(339), Phe(341), Tyr(342), and Tyr(344) in the human receptor; Phe(331), Ile(334), Trp(339), Phe(342), Phe(344), Phe(346), Tyr(347), and Tyr(349) in the rat receptor) located in the third extracellular loop, The seven aromatic residues form an aromatic pocket on the extracellular surface of the neurotensin receptor to accommodate its ligands apparently by cation-pi, pi-pi, and hydrogen bonding interactions, The neurotensin(8-13) ligand adopts a compact conformation at the proposed binding site, In the bound conformation of neurotensin(8-13), the backbone of Arg(9)-Pro(10)-Tyr(11)-Ile(12) forms the proline type I turn, and the hydroxy group of Tyr(11) interacts with the two guanidinium groups of Arg(8) and Arg(9). These guanidinium groups are curled toward the hydroxy group so that they interact electrostatically with the hydroxy group, and that the guanidinium group of Arg(9) forms an intra-hydrogen bond with the hydroxy group. The proposed three-dimensional structure may not only provide a basis for rationalizing mutations of the neurotensin receptor gene but also offer insights into understanding the binding of many neurotensin analogs, biological functions of the neurotensin receptors, and structural elements for species specificity of the neurotensin receptors, and may expedite developing nonpeptidic neurotensin mimetics for the potential treatment of the neuropsychiatric diseases.