Biased agonism at chemokine receptors.
Biased agonism at chemokine receptors.
复制标题
趋化因子受体的偏向激动作用。
DOI：
10.1016/j.cellsig.2020.109862
复制
发表时间：
2021-03
影响因子：
4.8
通讯作者：
Rajagopal S
中科院分区：
文献类型：
--
作者：
Eiger DS;Boldizsar N;Honeycutt CC;Gardner J;Rajagopal S
在人类趋化因子系统中，大约50种已知的内源性趋化因子配体和20种已知的趋化因子受体（CKRs）之间的相互作用调节着广泛的细胞功能和生物过程，包括免疫细胞激活和稳态、发育、血管生成和神经调节。CKRs是G蛋白偶联受体（GPCR）的一个家族，它代表了人类基因组中最常见和最通用的受体类别，并且是大约三分之一的食品和药物管理局批准的药物的靶标。趋化因子和ckr结合具有明显的混杂性，因为大多数ckr可以被多种趋化因子激活，大多数趋化因子可以激活多个ckr。虽然这些配体-受体相互作用以前被认为是多余的，但现在认识到许多趋化因子：CKR相互作用表现出偏向激动作用，即不同的配体通过不同的途径结合到相同的受体信号，具有不同的效果，导致不同的生物学效应。值得注意的是，这些偏倚反应可以通过配体、受体和或特定细胞环境（系统）的变化来调节。在这篇综述中，我们探讨了趋化因子系统中偏倚激动作用的生化机制、功能后果和治疗潜力。增强对趋化因子系统中偏倚激动作用的理解，可能会对理解所有GPCR亚型偏倚信号的机制和后果产生革命性的影响，并有助于开发具有更高治疗效果和更安全副作用的偏倚药物。
In the human chemokine system, interactions between the approximately 50 known endogenous chemokine ligands and 20 known chemokine receptors (CKRs) regulate a wide range of cellular functions and biological processes including immune cell activation and homeostasis, development, angiogenesis, and neuromodulation. CKRs are a family of G protein-coupled receptors (GPCR), which represent the most common and versatile class of receptors in the human genome and the targets of approximately one third of all Food and Drug Administration-approved drugs. Chemokines and CKRs bind with significant promiscuity, as most CKRs can be activated by multiple chemokines and most chemokines can activate multiple CKRs. While these ligand-receptor interactions were previously regarded as redundant, it is now appreciated that many chemokine:CKR interactions display biased agonism, the phenomenon in which different ligands binding to the same receptor signal through different pathways with different efficacies, leading to distinct biological effects. Notably, these biased responses can be modulated through changes in ligand, receptor, and or the specific cellular context (system). In this review, we explore the biochemical mechanisms, functional consequences, and therapeutic potential of biased agonism in the chemokine system. An enhanced understanding of biased agonism in the chemokine system may prove transformative in the understanding of the mechanisms and consequences of biased signaling across all GPCR subtypes and aid in the development of biased pharmaceuticals with increased therapeutic efficacy and safer side effect profiles.
登录
查看更多内容
影响因子：
3.7
作者：
Tubo NJ;Wurbel MA;Charvat TT;Schall TJ;Walters MJ;Campbell JJ
通讯作者：
Campbell JJ
影响因子：
3.6
作者：
Berchiche, Yamina A.;Sakmar, Thomas P.
通讯作者：
Sakmar, Thomas P.
DOI：
10.1073/pnas.1621280114
发表时间：
2017-06-06
影响因子：
11.1
作者：
Barsheshet, Yiftah;Wildbaum, Gizi;Karin, Nathan
通讯作者：
Karin, Nathan
影响因子：
5.5
作者：
Ameti, Rafet;Melgrati, Serena;Thelen, Marcus
通讯作者：
Thelen, Marcus
影响因子：
2.7
作者：
Abeywardane, Asitha;Caviness, Gary;Yu, Yang
通讯作者：
Yu, Yang