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

Abstract

Summary 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.

G protein-coupled receptors: structure- and function-based drug discovery

“…So far, four small molecules have been validated by crystallography to bind at this position. The targets are three chemokine receptors (CCR2, PDB code: 5T1A 192 ; CCR7, PDB code: 6QZH 193 ; and CCR9, PDB code: 5LWE 194 ) and β 2 AR (PDB code: 5X7D 195 ). These ligands are all NAMs and proximately share the same binding site (TM1, TM2, TM6, TM7, ICL1, and H8).…”

New insights into the structure and function of chemokine receptor:chemokine complexes from an experimental perspective

“…These structures confirmed that chemokine receptors have the canonical 7‐transmembrane GPCR fold with the extracellular end of the TM helices forming a wide orthosteric pocket to accommodate ligand binding . The initial, antagonist‐bound, CXCR4 structures have since been followed by structures of CCR2, CCR5, CCR7, and CCR9 all bound to different small molecule ligands as well as a structure of CCR5 bound to the HIV protein GP120 determined by cryo‐EM …”

Of Lymph Nodes and CLL Cells: Deciphering the Role of CCR7 in the Pathogenesis of CLL and Understanding Its Potential as Therapeutic Target

“…Recently, it was reported that allosteric antagonism by small molecules under clinical investigation interfered with CCL19-driven signaling ( 195 ). Thus this work confirmed a long-standing interest in active synthetic drugs to avoid entry of cancer cells into LN.…”