Please use this identifier to cite or link to this item:
http://hdl.handle.net/11375/30181
Full metadata record
DC Field | Value | Language |
---|---|---|
dc.contributor.author | García-Cuesta EM | - |
dc.contributor.author | Martínez P | - |
dc.contributor.author | Selvaraju K | - |
dc.contributor.author | Ulltjärn G | - |
dc.contributor.author | Gómez Pozo AM | - |
dc.contributor.author | D'Agostino G | - |
dc.contributor.author | Gardeta S | - |
dc.contributor.author | Quijada-Freire A | - |
dc.contributor.author | Blanco Gabella P | - |
dc.contributor.author | Roca C | - |
dc.contributor.author | Hoyo DD | - |
dc.contributor.author | Jiménez-Saiz R | - |
dc.contributor.author | García-Rubia A | - |
dc.contributor.author | Soler Palacios B | - |
dc.contributor.author | Lucas P | - |
dc.contributor.author | Ayala-Bueno R | - |
dc.contributor.author | Santander Acerete N | - |
dc.contributor.author | Carrasco Y | - |
dc.contributor.author | Oscar Sorzano C | - |
dc.contributor.author | Martinez A | - |
dc.contributor.author | Campillo NE | - |
dc.contributor.author | Jensen LD | - |
dc.contributor.author | Rodriguez Frade JM | - |
dc.contributor.author | Santiago C | - |
dc.contributor.author | Mellado M | - |
dc.date.accessioned | 2024-09-11T09:35:36Z | - |
dc.date.available | 2024-09-11T09:35:36Z | - |
dc.date.issued | 2024-09-09 | - |
dc.identifier.issn | 2050-084X | - |
dc.identifier.uri | http://hdl.handle.net/11375/30181 | - |
dc.description.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> | - |
dc.publisher | eLife Sciences Publications, Ltd | - |
dc.title | Allosteric modulation of the CXCR4:CXCL12 axis by targeting receptor nanoclustering via the TMV-TMVI domain | - |
dc.type | Article | - |
dc.date.updated | 2024-09-11T09:35:25Z | - |
dc.contributor.department | Medicine | - |
dc.identifier.doi | https://doi.org/10.7554/elife.93968.3 | - |
Appears in Collections: | Medicine Publications |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
elife-93968-v1.pdf | Published version | 8.69 MB | Adobe PDF | View/Open |
Items in MacSphere are protected by copyright, with all rights reserved, unless otherwise indicated.