Mapping the binding site of melanocortin 4 receptor agonists: A hydrophobic pocket formed by I3.28(125), I3.32(129), and I7.42(291) is critical for receptor activation
Mapping the binding site of melanocortin 4 receptor agonists: A hydrophobic pocket formed by I3.28(125), I3.32(129), and I7.42(291) is critical for receptor activation
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DOI：
10.1021/jm050780s
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发表时间：
2006-02-09
影响因子：
7.3
通讯作者：
Visiers, I
中科院分区：
文献类型：
--
作者：
Hogan, K;Peluso, S;Visiers, I
黑皮质素4受体参与摄食行为和能量稳态的控制。它由内部激动剂（α-MSH）和拮抗剂（Agglutamine）调节。肽激动剂以β-转角构象结合，所述β-转角构象将特征性信息序列（His-L/DPhe-Arg-Trp）组织成用于结合和活化受体的最佳排列。我们的目标是确定肽和小分子激动剂最可能的结合模式，以使用这些信息来指导我们基于结构的药物设计工作。以前的研究已经确定了一些残基可能参与肽激动剂结合，给出了肽和受体之间的主要接触的初步估计。然而，在结合位点中的P-转角构象中的肽的取向以及小分子激动剂的取向的更详细的描述，以及与肽激动剂结合模式的共性是必要的，以作为基于结构的药物设计的基础。在目前的研究中，我们将联合收割机定点突变与分子模拟研究相结合，以确定肽和小分子激动剂最可能的结合模式，我们发现Y6.58（268），Y7.38（287），13.28（125），13.32（129），和17.42（291）也排列在结合位点上，并可能与MC 4 R激动剂直接接触。特别感兴趣的是残基13.28（125）、13.32（129）和17.42（291），其形成疏水口袋，其中在NPXXY基序之上的17.42（291）可能充当与受体活化有关的新旋转异构体开关。
The melanocortin 4 receptor is involved in the control of the feeding behavior and energy homeostasis. It is regulated by internal agonist (alpha-MSH) and antagonists (Agouti). Peptide agonists bind in a beta-turn conformation that organizes the characteristic message sequence (His-L/DPhe-Arg-Trp) in an optimal arrangement for binding and activation of the receptor. Our goal is to determine the most likely binding modes of peptide and small molecule agonists to use this information to guide our structure-based drug design efforts. Previous studies have identified some residues that are likely to be involved in peptide agonist binding, giving an initial estimate of the main contacts between peptides and receptor. However, a more detailed description of the orientation of the peptide in a P-turn conformation in the binding site, as well as of the small molecule agonists, and it is commonalities with the peptide agonist binding modes is necessary to serve as the basis for structure-based drug design. In the current study we combine site-directed mutagenesis with molecular modeling studies to determine the most likely binding mode of peptide and small molecule agonists, and we found that Y6.58(268), Y7.38(287), 13.28(125), 13.32(129), and 17.42(291) also line the binding site and are likely to have direct contacts with the MC4R agonists. Of particular interest are residues 13.28(125), 13.32(129), and 17.42(29 1), which form a hydrophobic pocket where 17.42(29 1), on top of the NPXXY motif, is likely to act as a new rotamer switch implicated in the activation of the receptor.