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人源 CC 趋化因子受体 7 变构配体识别的结构基础。

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

机构信息

Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institute, Villigen PSI.

Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland.

出版信息

Cell. 2019 Aug 22;178(5):1222-1230.e10. doi: 10.1016/j.cell.2019.07.028.

DOI:10.1016/j.cell.2019.07.028
PMID:31442409
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6709783/
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 Å 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.

摘要

CC 趋化因子受体 7（CCR7）通过免疫细胞的稳态迁移来平衡免疫和耐受。在癌症中，CCR7 介导的迁移导致淋巴结转移，这表明该受体是一个有前途的治疗靶点。在这里，我们展示了通过使用高达 2.1Å 分辨率的数据，将人类 CCR7 与唾液酸酶 NanA 融合的晶体结构。该结构显示配体 Cmp2105 结合到细胞内变构结合口袋中。磺酰胺基团是各种趋化因子受体配体的特征，它结合在跨膜 7 螺旋和 8 螺旋之间的 Gi 蛋白结合区域的保守残基斑块上。我们展示了如何将结构数据与化合物库和自动热稳定性筛选结合使用，以识别和调节变构趋化因子受体拮抗剂。我们检测到新型（CS-1 和 CS-2）和临床相关（CXCR1-CXCR2 二期拮抗剂 Navarixin）CCR7 调节剂，这对针对癌症的多靶点策略具有重要意义。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/42fc/6709783/5eff7c186137/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/42fc/6709783/a6b8f226cff2/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/42fc/6709783/16175043aa97/figs1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/42fc/6709783/427a7f012c5e/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/42fc/6709783/842c07efa21f/figs2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/42fc/6709783/3d898f8a5a15/figs3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/42fc/6709783/a99867cae7b0/figs4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/42fc/6709783/7b32b68d1030/figs5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/42fc/6709783/ef2d0a6a9637/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/42fc/6709783/9c34340d7b63/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/42fc/6709783/56001ab360aa/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/42fc/6709783/5eff7c186137/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/42fc/6709783/a6b8f226cff2/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/42fc/6709783/16175043aa97/figs1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/42fc/6709783/427a7f012c5e/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/42fc/6709783/842c07efa21f/figs2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/42fc/6709783/3d898f8a5a15/figs3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/42fc/6709783/a99867cae7b0/figs4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/42fc/6709783/7b32b68d1030/figs5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/42fc/6709783/ef2d0a6a9637/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/42fc/6709783/9c34340d7b63/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/42fc/6709783/56001ab360aa/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/42fc/6709783/5eff7c186137/gr5.jpg

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