环状螯合素-9 肽和螯合素-S157 蛋白在 CMKLR 上的结合模式。

IF 2.6 4区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
ChemBioChem Pub Date : 2024-10-18 DOI:10.1002/cbic.202400695
Tina Schermeng, Fabian Liessmann, Carla Katharina Ambrosius, Jens Meiler, Annette G Beck-Sickinger
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引用次数: 0

摘要

趋化因子样受体 1(CMKLR1)是由脂肪因子和趋化蛋白螯合素激活的。螯合素-9-CMKLR1-Gi的冷冻电子显微镜结构已经公布,其中螯合素-9是螯合素S157 C末端的非肽。在 Ca2+ 释放方面,螯合素-9 与全长蛋白具有同样的活性,但在平衡读数方面存在差异。以前曾报道过一种同样有效的环状螯合素-9变体(cC9)。现在,我们建立了 CMKLR1 的计算模型,以研究 cC9 和 chemerinS157 与 chemerin-9 相比的结合模式。我们利用 CMKLR1 的变体研究了它们之间的差异。双突变周期分析确定 CMKLR1-F2.53 为 Phe8 与 cC9 结合的相关位置。能量贡献显示,Phe8 与 CMKLR1-F2.53 的结合略有不同,较大残基的空间也略有不同。这一点得到了证实,因为在第 8 位含有 1-萘基-L-丙氨酸的 chemerin-9 变体的效力增加了 4 倍,达到 2 nM(pEC50=8.6±0.15)。虽然chemerin-9和cC9在CMKLR1上有共同的相互作用,但chemerinS157能容忍CMKLR1深结合位点上的大多数突变。螯合素S157的计算模型表明,CMKLR1的N-端I25VVL28与ChemS157的β-sheet D108KVLGRLVH116之间存在β-sheet相互作用,实验证实了这一点。我们的数据通过确定ChemS157和cC9在CMKLR1上的结合模式扩展了知识,有助于未来基于结构的药物设计。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Binding Mode of Cyclic Chemerin-9 Peptide and ChemerinS157 Protein at CMKLR1.

The chemokine-like receptor 1 (CMKLR1) is activated by the adipokine and chemoattractant protein chemerin. Cryo-EM structures of chemerin-9-CMKLR1-Gi have been published, where chemerin-9 is the nonapeptide of the C terminus of chemerinS157. Chemerin-9 is as active as the full-length protein in Ca2+-release but shows differences in equilibrium read-outs. An equally potent cyclic chemerin-9 variant (cC9) was reported previously. Now, we have built a computational model of CMKLR1 to investigate the binding mode of cC9 and chemerinS157 in comparison to chemerin-9. Differences were investigated using CMKLR1 variants. Double-mutant cycle analysis identified CMKLR1-F2.53 as the relevant position for Phe8-binding of cC9. Energy contribution revealed slight differences in Phe8-binding to CMKLR1-F2.53 and space for larger residues. This was confirmed as the chemerin-9 variant with 1-naphthyl-L-alanine at position 8 showed a 4-fold increased potency of 2 nM (pEC50=8.6±0.15). While chemerin-9 and cC9 share their interactions at the CMKLR1, chemerinS157 tolerates most mutations of CMKLR1 in the deep binding site. The computational model of chemerinS157 suggests a β-sheet interaction between the N-terminal CMKLR1-segment I25VVL28 and the β-sheet D108KVLGRLVH116 of ChemS157, which was confirmed experimentally. Our data add to the knowledge by identifying the binding mode of chemerinS157 and cC9 at CMKLR1, facilitating the future structure-based drug design.

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来源期刊
ChemBioChem
ChemBioChem 生物-生化与分子生物学
CiteScore
6.10
自引率
3.10%
发文量
407
审稿时长
1 months
期刊介绍: ChemBioChem (Impact Factor 2018: 2.641) publishes important breakthroughs across all areas at the interface of chemistry and biology, including the fields of chemical biology, bioorganic chemistry, bioinorganic chemistry, synthetic biology, biocatalysis, bionanotechnology, and biomaterials. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies, and supported by the Asian Chemical Editorial Society (ACES).
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