Elife 2024 Sep 9:13:RP93968.
García-Cuesta EM, Martínez P, Selvaraju K, Ulltjärn G, Gómez Pozo AM, D’Agostino G, Gardeta S, Quijada-Freire A, Blanco Gabella P, Roca C, Hoyo DD, Jiménez-Saiz R, García-Rubia A, Soler Palacios B, Lucas P, Ayala-Bueno R, Santander Acerete N, Carrasco Y, Oscar Sorzano C, Martinez A, Campillo NE, Jensen LD, Rodriguez Frade JM, Santiago C, Mellado M.
Abstract
CXCR4 is a ubiquitously expressed chemokine receptor that regulates leukocyte trafficking and arrest in both homeostatic and pathological states. It also participates in organogenesis, HIV-1 infection, and tumor development. Despite the potential therapeutic benefit of CXCR4 antagonists, only one, plerixafor (AMD3100), which blocks the ligand-binding site, has reached the clinic. Recent advances in imaging and biophysical techniques have provided a richer understanding of the membrane organization and dynamics of this receptor. Activation of CXCR4 by CXCL12 reduces the number of CXCR4 monomers/dimers at the cell membrane and increases the formation of large nanoclusters, which are largely immobile and are required for correct cell orientation to chemoattractant gradients. Mechanistically, CXCR4 activation involves a structural motif defined by residues in TMV and TMVI. Using this structural motif as a template, we performed in silico molecular modeling followed by in vitro screening of a small compound library to identify negative allosteric modulators of CXCR4 that do not affect CXCL12 binding. We identified AGR1.137, a small molecule that abolishes CXCL12-mediated receptor nanoclustering and dynamics and blocks the ability of cells to sense CXCL12 gradients both in vitro and in vivo while preserving ligand binding and receptor internalization.
DOI: 10.7554/eLife.93968