瑞士保罗谢尔研究所Joerg Standfuss研究组与罗氏公司Roger J.P. Dawson团队合作解析了CCR7变构识别配体的结构基础。相关论文于2019年8月22日发表于国际学术期刊《细胞》。

研究人员通过使用高达2.1分辨率的数据呈现了人类CCR7与蛋白质唾液酸酶NanA融合的晶体结构。该结构显示配体Cmp2105与细胞内变构结合口袋结合。磺胺基团是各种趋化因子受体配体的特征，它与跨膜螺旋7和螺旋8之间的Gi蛋白结合区域中的一片保守残基结合。研究人员展示了结构数据如何与化合物库和自动热稳定性结合从而筛选鉴定和调节变构趋化因子受体的拮抗剂。研究人员检测到新的（CS-1和CS-2）以及临床相关的（CXCR1-CXCR2 II期拮抗剂Navarixin）CCR7调节剂，这对多把点抗癌具有意义。

据了解，CC趋化因子受体7（CCR7）通过免疫细胞的稳态运输来平衡免疫和耐受。在癌症中，CCR7介导的运输导致淋巴结转移，表明该受体是有希望的治疗靶标。

附：英文原文

Title: Structural Basis for Allosteric Ligand Recognition in the Human CC Chemokine Receptor 7

Author: Kathrin Jaeger,Steffen Bruenle,Tobias Weinert,Wolfgang Guba,Jonas Muehle

Takuya Miyazaki,Martin Weber,Antonia Furrer,Noemi Haenggi,Tim Tetaz,Chia-Ying Huang,Daniel Mattle,Jean-Marie Vonach,Alain Gast,Andreas Kuglstatter,Markus G. Rudolph,Przemyslaw Nogly,Joerg Benz,Roger J.P. Dawson,Joerg Standfuss

Issue&Volume: Volume 178 Issue 5

Abstract: The CC chemokine receptor 7 (CCR7) balances immunity and tolerance by homeostatic trafficking of immune cells. In cancer, CCR7-mediated trafficking leads to lymph node metastasis, suggesting the receptor as a promising therapeutic target. Here, we present the crystal structure of human CCR7 fused to the protein Sialidase NanA by using data up to 2.1 resolution. The structure shows the ligand Cmp2105 bound to an intracellular allosteric binding pocket. A sulfonamide group, characteristic for various chemokine receptor ligands, binds to a patch of conserved residues in the Gi protein binding region between transmembrane helix 7 and helix 8. We demonstrate how structural data can be used in combination with a compound repository and automated thermal stability screening to identify and modulate allosteric chemokine receptor antagonists. We detect both novel (CS-1 and CS-2) and clinically relevant (CXCR1-CXCR2 phase-II antagonist Navarixin) CCR7 modulators with implications for multi-target strategies against cancer.

DOI: https://doi.org/10.1016/j.cell.2019.07.028

Source: https://www.cell.com/cell/fulltext/S0092-8674(19)30795-0