Please use this identifier to cite or link to this item:
http://hdl.handle.net/11375/30181
Title: | Allosteric modulation of the CXCR4:CXCL12 axis by targeting receptor nanoclustering via the TMV-TMVI domain |
Authors: | 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 |
Department: | Medicine |
Publication Date: | 9-Sep-2024 |
Publisher: | eLife Sciences Publications, Ltd |
Abstract: | <jats:p>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.</jats:p> |
URI: | http://hdl.handle.net/11375/30181 |
metadata.dc.identifier.doi: | https://doi.org/10.7554/elife.93968.3 |
ISSN: | 2050-084X |
Appears in Collections: | Medicine Publications |
Files in This Item:
File | Description | Size | Format | |
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elife-93968-v1.pdf | Published version | 8.69 MB | Adobe PDF | View/Open |
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