6QZH

Structure of the human CC Chemokine Receptor 7 in complex with the intracellular allosteric antagonist Cmp2105 and the insertion protein Sialidase NanA

Summary for 6QZH

• Entry DOI: 10.2210/pdb6qzh/pdb
• Descriptor: C-C chemokine receptor type 7,Sialidase A,C-C chemokine receptor type 7, TRIETHYLENE GLYCOL, 3-[[4-[[(1~{R})-2,2-dimethyl-1-(5-methylfuran-2-yl)propyl]amino]-1,1-bis(oxidanylidene)-1,2,5-thiadiazol-3-yl]amino]-~{N},~{N},6-trimethyl-2-oxidanyl-benzamide, ... (6 entities in total)
• Functional Keywords: gpcr, chemokine receptor, small molecule, allosteric modulator, insertion protein, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 1
• Total formula weight: 89289.41

Authors

Jaeger, K.,Bruenle, S.,Weinert, T.,Guba, W.,Muehle, J.,Miyazaki, T.,Weber, M.,Furrer, A.,Haenggi, N.,Tetaz, T.,Huang, C.Y.,Mattle, D.,Vonach, J.M.,Gast, A.,Kuglstatter, A.,Rudolph, M.G.,Nogly, P.,Benz, J.,Dawson, R.J.P.,Standfuss, J. (deposition date: 2019-03-11, release date: 2019-09-04, Last modification date: 2024-11-06)

Primary citation

Jaeger, K.,Bruenle, S.,Weinert, T.,Guba, W.,Muehle, J.,Miyazaki, T.,Weber, M.,Furrer, A.,Haenggi, N.,Tetaz, T.,Huang, C.Y.,Mattle, D.,Vonach, J.M.,Gast, A.,Kuglstatter, A.,Rudolph, M.G.,Nogly, P.,Benz, J.,Dawson, R.J.P.,Standfuss, J.
Structural Basis for Allosteric Ligand Recognition in the Human CC Chemokine Receptor 7.
Cell, 178:1222-1230.e10, 2019

PubMed 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.

PubMed: 31442409
DOI: 10.1016/j.cell.2019.07.028

Experimental method

X-RAY DIFFRACTION (2.1 Å)