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- Title
Allosteric modulation of the CXCR4:CXCL12 axis by targeting receptor nanoclustering via the TMV-TMVI domain.
- Authors
García-Cuesta, Eva M.; Martínez, Pablo; Selvaraju, Karthik; Ulltjärn, Gabriel; Gómez Pozo, Adrián Miguel; D'Agostino, Gianluca; Gardeta, Sofia; Quijada-Freire, Adriana; Blanco Gabella, Patricia; Roca, Carlos; del Hoyo, Daniel; Jiménez-Saiz, Rodrigo; García-Rubia, Alfonso; Soler Palacios, Blanca; Lucas, Pilar; Ayala-Bueno, Rosa; Santander Acerete, Noelia; Carrasco, Yolanda; Sorzano, Carlos Oscar; Martinez, Ana
- Abstract
CXCR4 is a ubiquitously expressed chemokine receptor that regulates leukocyte traf- ficking 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.
- Subjects
CELL membrane formation; LIGAND binding (Biochemistry); CHEMICAL libraries; CXCR4 receptors; ALLOSTERIC regulation
- Publication
eLife, 2024, p1
- ISSN
2050-084X
- Publication type
Article
- DOI
10.7554/eLife.93968