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.
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6 October 2014
INTERNATIONAL CONFERENCE OF COMPUTATIONAL METHODS IN SCIENCES AND ENGINEERING 2014 (ICCMSE 2014)
4–7 April 2014
Athens, Greece
Research Article|
October 06 2014
Polypharmacology within CXCR4: Multiple binding sites and allosteric behavior
Jesús M. Planesas;
Jesús M. Planesas
Grup d'Enginyeria Molecular, Institut Químic de Sarriá (IQS), Universitat Ramon Llull, Barcelona,
Spain
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Violeta I. Pérez-Nueno;
Violeta I. Pérez-Nueno
Grup d'Enginyeria Molecular, Institut Químic de Sarriá (IQS), Universitat Ramon Llull, Barcelona, Spain and Harmonic Pharma, 615 rue du Jardin Botanique, 54600 Villers lès Nancy,
France
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José I. Borrell;
José I. Borrell
Grup d'Enginyeria Molecular, Institut Químic de Sarriá (IQS), Universitat Ramon Llull, Barcelona,
Spain
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Jordi Teixidó
Jordi Teixidó
Grup d'Enginyeria Molecular, Institut Químic de Sarriá (IQS), Universitat Ramon Llull, Barcelona,
Spain
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AIP Conf. Proc. 1618, 1036–1038 (2014)
Citation
Jesús M. Planesas, Violeta I. Pérez-Nueno, José I. Borrell, Jordi Teixidó; Polypharmacology within CXCR4: Multiple binding sites and allosteric behavior. AIP Conf. Proc. 6 October 2014; 1618 (1): 1036–1038. https://doi.org/10.1063/1.4898789
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