Polypharmacology within CXCR4: Multiple binding sites and allosteric behavior

Jesús M. Planesas, Violeta I. Pérez-Nueno, José I. Borrell, Jordi Teixidó

Producción científica: Capítulo del libroContribución a congreso/conferenciarevisión exhaustiva

Resumen

CXCR4 is a promiscuous receptor, which binds multiple diverse ligands. As usual in promiscuous proteins, CXCR4 has a large binding site, with multiple subsites, and high flexibility. Hence, it is not surprising that it is involved in the phenomenon of allosteric modulation. However, incomplete knowledge of allosteric ligand-binding sites has hampered an in-depth molecular understanding of how these inhibitors work. For example, it is known that lipidated fragments of intracellular GPCR loops, so called pepducins, such as pepducin ATI-2341, modulate CXCR4 activity using an agonist allosteric mechanism. Nevertheless, there are also examples of small organic molecules, such as AMD11070 and GSK812397, which may act as antagonist allosteric modulators. Here, we give new insights into this issue by proposing the binding interactions between the CXCR4 receptor and the above-mentioned allosteric modulators. We propose that CXCR4 has minimum two topographically different allosteric binding sites. One allosteric site would be in the intracellular loop 1 (ICL1) where pepducin ATI-2341 would bind to CXCR4, and the second one, in the extracellular side of CXCR4 in a subsite into the main orthosteric binding pocket, delimited by extracellular loops n° 1, 2, and the N-terminal end, where antagonists AMD11070 and GSK812397 would bind. Prediction of allosteric interactions between CXCR4 and pepducin ATI-2341 were studied first by rotational blind docking to determine the main binding region and a subsequent refinement of the best pose was performed using flexible docking methods and molecular dynamics. For the antagonists AMD11070 and GSK812397, the entire CXCR4 protein surface was explored by blind docking to define the binding region. A second docking analysis by subsites of the identified binding region was performed to refine the allosteric interactions. Finally, we identified the binding residues that appear to be essential for CXCR4 (agonists and antagonists) allosteric modulators.

Idioma originalInglés
Título de la publicación alojadaInternational Conference of Computational Methods in Sciences and Engineering 2014, ICCMSE 2014
EditoresTheodore E. Simos, Theodore E. Simos, Theodore E. Simos, Theodore E. Simos, Theodore E. Simos, Zacharoula Kalogiratou, Theodore Monovasilis
EditorialAmerican Institute of Physics Inc.
Páginas1036-1038
Número de páginas3
ISBN (versión digital)9780735412552
DOI
EstadoPublicada - 6 oct 2014
EventoInternational Conference of Computational Methods in Sciences and Engineering 2014, ICCMSE 2014 - Athens, Grecia
Duración: 4 abr 20147 abr 2014

Serie de la publicación

NombreAIP Conference Proceedings
Volumen1618
ISSN (versión impresa)0094-243X
ISSN (versión digital)1551-7616

Conferencia

ConferenciaInternational Conference of Computational Methods in Sciences and Engineering 2014, ICCMSE 2014
País/TerritorioGrecia
CiudadAthens
Período4/04/147/04/14

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