Allosteric modulation of the CXCR4:CXCL12 axis by targeting receptor nanoclustering via the TMV-TMVI domain
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.
Authors
- Blanca Soler Palacios (ORCID: https://orcid.org/0000-0001-6031-1896)
- Adriana Quijada‐Freire (ORCID: https://orcid.org/0000-0001-6709-5620)
- Pilar Lucas
- Carlos Óscar S. Sorzano (ORCID: https://orcid.org/0000-0002-9473-283X)
- Nuria Eugenia Campillo (ORCID: https://orcid.org/0000-0002-9948-2665)
- Rodrigo Jiménez‐Saiz (ORCID: https://orcid.org/0000-0002-0606-3251)
- José Miguel Rodríguez‐Frade (ORCID: https://orcid.org/0000-0002-7753-1462)
- Alfonso García‐Rubia
- Lasse D. Jensen (ORCID: https://orcid.org/0000-0003-2338-357X)
- Gianluca D’Agostino (ORCID: https://orcid.org/0000-0002-7346-9278)
- Ana Martı́nez (ORCID: https://orcid.org/0000-0002-2707-8110)
- Karthik Selvaraju (ORCID: https://orcid.org/0000-0002-6206-9850)
- Daniel del Hoyo (ORCID: https://orcid.org/0009-0005-3321-1810)
- Mario Mellado (ORCID: https://orcid.org/0000-0001-6325-1630)
- Sofía R. Gardeta (ORCID: https://orcid.org/0000-0003-1166-4809)
- Yolanda R. Carrasco (ORCID: https://orcid.org/0000-0003-2148-1926)
- Rosa Ayala-Bueno (ORCID: https://orcid.org/0000-0002-7902-2784)
- Eva M. García‐Cuesta (ORCID: https://orcid.org/0000-0003-2311-4353)
- César Santiago (ORCID: https://orcid.org/0000-0002-5149-1722)
- Noelia Santander Acerete
- Adrián Miguel Gómez Pozo
- Patricia Blanco Gabella
- Carlos Roca (ORCID: https://orcid.org/0000-0002-6666-709X)
- Pablo Martínez (ORCID: https://orcid.org/0000-0002-2048-4837)
- Gabriel Ulltjärn
Institutions
- Linköping University (SE)
- Universidad Francisco de Vitoria (ES)
- Instituto de Salud Carlos III (ES)
- Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
- Centro Nacional de Biotecnología (ES)
- Hospital Universitario de La Princesa (ES)
- Centro de Investigaciones Biológicas Margarita Salas (ES)
- Biocom (US)
- McMaster University (CA)
Publication Details
- Journal
- eLife
- Published
- 2024-09-09
- DOI
- https://doi.org/10.7554/elife.93968.3
- Citations
- 8
- Primary Topic
- Chemokine receptors and signaling
- Type
- article
- Field-Weighted Citation Impact
- 2.26
Funders
- Comunidad de Madrid
- Universidad Autónoma de Madrid
- Ministerio de Ciencia e Innovación
- Instituto de Salud Carlos III
- European Regional Development Fund
- Agencia Estatal de Investigación
- Spanish National Plan for Scientific and Technical Research and Innovation