Aijun Liu, Yezhou Liu, Geng Chen, Wenping Lyu, Fang Ye, Junlin Wang, Qiwen Liao, Lizhe Zhu, Yang Du, Richard D Ye
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引用次数: 0
摘要
螯合素是一种脂肪因子,对部分白细胞具有趋化活性。螯合素与 3 种 G 蛋白偶联受体结合,包括趋化因子样受体 1(CMKLR1)、G 蛋白偶联受体 1(GPR1)和 C-C 趋化因子样受体 2(CCRL2)。在这里,我们报告了 GPR1 在全长螯合素或其 C 端非肽(C9,YFPGQFAFS)的刺激下能够发出 Gi 信号。我们展示了分别与全长螯合素和 C9 肽结合的 Gi 偶联 GPR1 的高分辨率冷冻电镜结构。C9 插入跨膜(TM)结合口袋对于 GPR1 信号传导是必要且充分的,而全长螯合素则利用其笨重的 N 端核心与位于 GPR1 N 端的 β 链相互作用。这种相互作用涉及到全长螯合素的多条 β 链,形成了一个 β 片层,作为 TM 结合袋的 "盖子",根据分子动力学模拟和自由能谱分析,去除它的能量代价很高。结合功能测试的结果,我们的结构模型解释了为什么 C9 是 GPR1 的激活肽,以及全长螯合素如何使用 "双位点 "模型来增强与 GPR1 的相互作用。
Structure of G protein-coupled receptor GPR1 bound to full-length chemerin adipokine reveals a chemokine-like reverse binding mode.
Chemerin is an adipokine with chemotactic activity to a subset of leukocytes. Chemerin binds to 3 G protein-coupled receptors, including chemokine-like receptor 1 (CMKLR1), G protein-coupled receptor 1 (GPR1), and C-C chemokine receptor-like 2 (CCRL2). Here, we report that GPR1 is capable of Gi signaling when stimulated with full-length chemerin or its C-terminal nonapeptide (C9, YFPGQFAFS). We present high-resolution cryo-EM structures of Gi-coupled GPR1 bound to full-length chemerin and to the C9 peptide, respectively. C9 insertion into the transmembrane (TM) binding pocket is both necessary and sufficient for GPR1 signaling, whereas the full-length chemerin uses its bulky N-terminal core for interaction with a β-strand located at the N-terminus of GPR1. This interaction involves multiple β-strands of full-length chemerin, forming a β-sheet that serves as a "lid" for the TM binding pocket and is energetically expensive to remove as indicated by molecular dynamics simulations with free energy landscape analysis. Combining results from functional assays, our structural model explains why C9 is an activating peptide at GPR1 and how the full-length chemerin uses a "two-site" model for enhanced interaction with GPR1.
期刊介绍:
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