Structures of the CXCR4 Chemokine GPCR with Small-Molecule and Cyclic Peptide Antagonists

TLDR

Cell migration driven by chemokine receptors such as CXCR4, a GPCR involved in cancer and infection, is a key factor in disease progression. The study presents crystal structures of CXCR4 bound to small‑molecule antagonists. All structures revealed a consistent homodimer interface, indicating functional relevance and providing insights into CXCR4 interactions with its chemokine ligand and HIV‑1. Published online 7 October, page 1066.

Abstract

Regulating Migration The migration of cells around the body is an important factor in cancer development and the establishment of infection. Movement is induced by small proteins called chemokines, and so for a specific function, migration is controlled by a relevant chemokine binding to its respective receptor. This family of receptors is known as guanine (G) protein–coupled receptors, which span cell membranes to mediate between external signals from chemokines and internal mechanisms. The chemokine receptor CXCR4 is implicated in many types of cancer and in infection, and Wu et al. (p. 1066 , published online 7 October; see the Report by Chien et al. ) report on a series of crystal structures obtained for CXCR4 bound to small molecules. In every case, the same homodimer structure was observed, suggesting that the interface is functionally relevant. These structures offer insights into the interactions between CXCR4 and its natural chemokine, as well as with the virus HIV-1.