Polypharmacology within CXCR4: Multiple binding sites and allosteric behavior

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

Producció científica: Capítol de llibreContribució a congrés/conferènciaAvaluat per experts

Resum

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 originalAnglès
Títol de la publicacióInternational Conference of Computational Methods in Sciences and Engineering 2014, ICCMSE 2014
EditorsTheodore E. Simos, Theodore E. Simos, Theodore E. Simos, Theodore E. Simos, Theodore E. Simos, Zacharoula Kalogiratou, Theodore Monovasilis
EditorAmerican Institute of Physics Inc.
Pàgines1036-1038
Nombre de pàgines3
ISBN (electrònic)9780735412552
DOIs
Estat de la publicacióPublicada - 6 d’oct. 2014
EsdevenimentInternational Conference of Computational Methods in Sciences and Engineering 2014, ICCMSE 2014 - Athens, Greece
Durada: 4 d’abr. 20147 d’abr. 2014

Sèrie de publicacions

NomAIP Conference Proceedings
Volum1618
ISSN (imprès)0094-243X
ISSN (electrònic)1551-7616

Conferència

ConferènciaInternational Conference of Computational Methods in Sciences and Engineering 2014, ICCMSE 2014
País/TerritoriGreece
CiutatAthens
Període4/04/147/04/14

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