CMKLR1与chemerin及α-NETA复合体结构预测

CMKLR1 with Chemerin or α-NETA Complex Structure Predict

他扎罗替尼诱导基因2(tazarotene-induced gene 2,TIG2)的产物chemerin是孤儿G蛋白耦联受体趋化因子样受体1(chemokine-like receptor 1,CMKLR1)的内源性配体。chemerin/CMKLR1信号系统在体内多组织器官发挥着重要的功能和作用。chemerin的C端在体内被蛋白酶切后形成多种亚型,该文通过Alphafold2对chemerin的6种亚型进行结构预测与建模,并将其中有活性的3种形式与CMKLR1进行复合体建模,对复合体进行结合位点分析后,阐明不同活性形式的差异结合位点。此外,将CMKLR1的小分子拮抗剂2-(α-萘甲酰基)乙基三甲基碘化铵(2-(α-naphthoyl)ethyltrimethylammonium iodide,α-NETA)与CMKLR1进行对接,确定二者的相互结合位置。实验结果从蛋白质分子结构层面解释了两点:(1)具有活性的chemerin与CMKLR1的互作方式;(2)小分子拮抗剂α-NETA与CMKLR1的互作方式。研究内容将为CMKLR1的靶向药物设计提供理论依据和实验基础。

Chemerin,derived from tazarotenib-induced gene 2(TIG2),is an endogenous ligand for the orphan G protein-coupled receptor chemokine-like receptor 1(CMKLR1).Chemerin/CMKLR1 signaling system plays an important role in multiple tissues and organs,and there are multiple chemerin isoforms in vivo due to the C-terminal proteolysis by several proteases.This paper predicted and modeled the structure of six isoforms of chemerin by Alphafold2,and modeled three active isoforms in complex with CMKLR1,to elucidate the different binding sites of different isoforms.Additionally,the known small molecule antagonist of CMKLR1,2-(α-naphthoyl)ethyltrimethylammonium iodide(α-NETA),was also modeled to dock with CMKLR1,and the binding sites of aα-NETA with CMKLR1 were analyzed.From the protein molecular structure level,our results provide:(1)The mode of interaction between active chemerin and CMKLRl;(2)The mode of interaction betweenα-NETA and CMKLR1.This study provides theoretical basis and experimental basis for the design of targeted drugs for CMKLR1.