Selectivity and antagonism of chemokine receptors
Selectivity and antagonism of chemokine receptors
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DOI：
10.1002/jlb.59.1.53
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发表时间：
1996-01-01
影响因子：
5.5
通讯作者：
Proudfoot, AEI
中科院分区：
文献类型：
--
作者：
Wells, TNC;Power, CA;Proudfoot, AEI
根据氨基末端半胱氨酸间距，趋化因子超家族可分为两类。CXC 趋化因子主要参与中性粒细胞介导的炎症，迄今为止，已克隆了两种人类受体。 CC趋化因子往往与慢性炎症有关，最近我们克隆了这组配体的第四种白细胞受体。如果我们要开发有效的选择性拮抗剂，了解是什么使一种受体与其一系列激动剂结合非常重要。我们已经开始通过研究为什么 CC 趋化因子不以多种方式与 CXC 受体结合来研究这种受体选择性的分子基础。首先，我们研究了配体的三维结构的作用，并使用核磁共振波谱解析了 RANTES 的三维结构，该结构与已经确定的 CC 趋化因子巨噬细胞炎症的结构相似。 Protein-1 beta，它与 CXC 趋化因子 IL-8 (IL-8) 具有完全不同的二聚体界面，然而，所有趋化因子的单体结构都非常相似，并且在生理浓度下蛋白质很可能是单体的，其次，通过检查所有已知的 CC 和 CXC 趋化因子，我们发现了两个亚家族之间存在差异的区域，该区域中的残基之一 Leu-25 发生突变IL-8，酪氨酸（在CC趋化因子的这个位置保守）使突变的IL-8能够结合CC趋化因子受体1（CC-CKR-1）并引入单核细胞趋化活性，利用该区域的其他突变，我们可以显示与CC-CKR-1的N末端的直接相互作用，第三，我们发现通过添加一个氨基酸对RANTES的氨基末端进行修饰使其成为拮抗剂总而言之，这些数据表明了受体激活以及 CC 和 CXC 趋化因子之间选择性的双位点模型，其中初始受体接触由趋化因子主体提供，激活由氨基末端区域提供。
The chemokine superfamily can be subdivided into two groups based on their amino terminal cysteine spacing, The CXC chemokines are primarily involved in neutrophil-mediated inflammation and, so far, two human receptors have been cloned. The CC chemokines tend to be involved in chronic inflammation, and recently we have cloned a fourth leukocyte receptor for this group of ligands. Understanding what makes one receptor bind its range of agonists is important if we are to develop potent selective antagonists, We have started to investigate the molecular basis of this receptor selectivity by looking at why CC chemokines do not bind to the CXC receptors in several ways, First, we looked at the role of the three-dimensional structure of the ligand, and have solved the three-dimensional structure of RANTES using nuclear magnetic: resonance spectroscopy, The structure is similar to that already determined for the CC chemokine macrophage inflammatory protein-1 beta, and it has a completely different dimer interface to that of the CXC chemokine interleukin-8 (IL-8), However, the monomer structures of all the chemokines are very similar, and at physiological concentrations the proteins are likely to be monomeric, Second, by examining all the known CC and CXC chemokines, we have found a region that differs between the two subfamilies, Mutations of one of the residues in this region, Leu-25 in IL-8, to tyrosine (which is conserved at this position in CC chemokines) enables the mutant IL-8 to bind CC-chemokine receptor-1 (CC-CKR-1) and introduces monocyte chemoattractant activity, Using other mutations in this region, we can show a direct interaction with the N-terminus of CC-CKR-1, Third, we have found that modification of the amino termimus of RANTES by addition of one amino acid makes it into an antagonist with nanomolar potency, Taken together, this data suggests a two-site model for receptor activation and for selectivity between CC and CXC chemokines, with an initial receptor contact provided by the main body of the chemokine, and activation provided by the amino terminal region.