Abstract：
Chemokine receptors are integral to the immune system and prime targets in drug discovery that have undergone extensive structural elucidation in recent years. We outline a timeline of these structural achievements, discuss the intracellular negative allosteric modulation of chemokine receptors, analyze the mechanisms of orthosteric receptor activation, and report on the emerging concept of biased signaling. Additionally, we highlight differences of G-protein binding among chemokine receptors. Intracellular allosteric modulators in chemokine receptors interact with a conserved motif within transmembrane helix 7 and helix 8 and exhibit a two-fold inactivation mechanism that can be harnessed for drug-discovery efforts. Chemokine recognition is a multi-step process traditionally explained by a two-site model within chemokine recognition site 1 (CRS1) and CRS2. Recent structural studies have extended our understanding of this complex mechanism with the identification of CRS1.5 and CRS3. CRS3 is implicated in determining ligand specificity and surrounds the chemokine by almost 180°. Within CRS3 we identified the extracellular loop 2 residue 45.51 as a key interaction mediator for chemokine binding. Y2917.43 on the other hand was shown in CCR1 to be a key determinant of signaling bias which, along with specific chemokine-dependent phosphorylation ensembles at the G-protein coupled receptors (GPCR\'s) C-terminus, seems to play a pivotal role in determining the direction of signal bias in GPCRs.
摘要：
趋化因子受体是免疫系统不可或缺的组成部分，并且是药物发现中的主要靶标，近年来已对其进行了广泛的结构阐明。我们概述了这些结构性成就的时间表，讨论趋化因子受体的细胞内负变构调制，分析正构受体激活的机制，并报告了有偏见信号的新兴概念。此外,我们强调了趋化因子受体之间G蛋白结合的差异。趋化因子受体中的细胞内变构调节剂与跨膜螺旋7和螺旋8内的保守基序相互作用，并表现出双重失活机制，可用于药物发现工作。趋化因子识别是传统上由趋化因子识别位点1(CRS1)和CRS2内的双位点模型解释的多步骤过程。最近的结构研究通过鉴定CRS1.5和CRS3扩展了我们对这种复杂机制的理解。CRS3与确定配体特异性有关，并围绕趋化因子几乎180°。在CRS3中,我们将细胞外环2残基45.51鉴定为趋化因子结合的关键相互作用介质。另一方面，Y2917.43在CCR1中显示为信号传导偏差的关键决定因素，连同G蛋白偶联受体（GPCR）C端的特异性趋化因子依赖性磷酸化集合，似乎在确定GPCR中信号偏差的方向中起着关键作用。
