Cargando…

Structural Basis of the Binding Mode of the Antineoplastic Compound Motixafortide (BL-8040) in the CXCR4 Chemokine Receptor

Modulation of the CXCL12–CXCR4 signaling axis is of the utmost importance due to its central involvement in several pathological disorders, including inflammatory diseases and cancer. Among the different currently available drugs that inhibit CXCR4 activation, motixafortide—a best-in-class antagonis...

Descripción completa

Detalles Bibliográficos
Autores principales: Rebolledo-Bustillo, Mariana, Garcia-Gomez, David, Dávila, Eliud Morales, Castro, María Eugenia, Caballero, Norma A., Melendez, Francisco J., Baizabal-Aguirre, Victor M., Sanchez-Gaytan, Brenda L., Perez-Aguilar, Jose Manuel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10001991/
https://www.ncbi.nlm.nih.gov/pubmed/36901829
http://dx.doi.org/10.3390/ijms24054393
_version_ 1784904280317100032
author Rebolledo-Bustillo, Mariana
Garcia-Gomez, David
Dávila, Eliud Morales
Castro, María Eugenia
Caballero, Norma A.
Melendez, Francisco J.
Baizabal-Aguirre, Victor M.
Sanchez-Gaytan, Brenda L.
Perez-Aguilar, Jose Manuel
author_facet Rebolledo-Bustillo, Mariana
Garcia-Gomez, David
Dávila, Eliud Morales
Castro, María Eugenia
Caballero, Norma A.
Melendez, Francisco J.
Baizabal-Aguirre, Victor M.
Sanchez-Gaytan, Brenda L.
Perez-Aguilar, Jose Manuel
author_sort Rebolledo-Bustillo, Mariana
collection PubMed
description Modulation of the CXCL12–CXCR4 signaling axis is of the utmost importance due to its central involvement in several pathological disorders, including inflammatory diseases and cancer. Among the different currently available drugs that inhibit CXCR4 activation, motixafortide—a best-in-class antagonist of this GPCR receptor—has exhibited promising results in preclinical studies of pancreatic, breast, and lung cancers. However, detailed information on the interaction mechanism of motixafortide is still lacking. Here, we characterize the motixafortide/CXCR4 and CXCL12/CXCR4 protein complexes by using computational techniques including unbiased all-atom molecular dynamics simulations. Our microsecond-long simulations of the protein systems indicate that the agonist triggers changes associated with active-like GPCR conformations, while the antagonist favors inactive conformations of CXCR4. Detailed ligand–protein analysis indicates the importance of motixafortide’s six cationic residues, all of which established charge–charge interactions with acidic CXCR4 residues. Furthermore, two synthetic bulky chemical moieties of motixafortide work in tandem to restrict the conformations of important residues associated with CXCR4 activation. Our results not only elucidate the molecular mechanism by which motixafortide interacts with the CXCR4 receptor and stabilizes its inactive states, but also provide essential information to rationally design CXCR4 inhibitors that preserve the outstanding pharmacological features of motixafortide.
format Online
Article
Text
id pubmed-10001991
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-100019912023-03-11 Structural Basis of the Binding Mode of the Antineoplastic Compound Motixafortide (BL-8040) in the CXCR4 Chemokine Receptor Rebolledo-Bustillo, Mariana Garcia-Gomez, David Dávila, Eliud Morales Castro, María Eugenia Caballero, Norma A. Melendez, Francisco J. Baizabal-Aguirre, Victor M. Sanchez-Gaytan, Brenda L. Perez-Aguilar, Jose Manuel Int J Mol Sci Article Modulation of the CXCL12–CXCR4 signaling axis is of the utmost importance due to its central involvement in several pathological disorders, including inflammatory diseases and cancer. Among the different currently available drugs that inhibit CXCR4 activation, motixafortide—a best-in-class antagonist of this GPCR receptor—has exhibited promising results in preclinical studies of pancreatic, breast, and lung cancers. However, detailed information on the interaction mechanism of motixafortide is still lacking. Here, we characterize the motixafortide/CXCR4 and CXCL12/CXCR4 protein complexes by using computational techniques including unbiased all-atom molecular dynamics simulations. Our microsecond-long simulations of the protein systems indicate that the agonist triggers changes associated with active-like GPCR conformations, while the antagonist favors inactive conformations of CXCR4. Detailed ligand–protein analysis indicates the importance of motixafortide’s six cationic residues, all of which established charge–charge interactions with acidic CXCR4 residues. Furthermore, two synthetic bulky chemical moieties of motixafortide work in tandem to restrict the conformations of important residues associated with CXCR4 activation. Our results not only elucidate the molecular mechanism by which motixafortide interacts with the CXCR4 receptor and stabilizes its inactive states, but also provide essential information to rationally design CXCR4 inhibitors that preserve the outstanding pharmacological features of motixafortide. MDPI 2023-02-23 /pmc/articles/PMC10001991/ /pubmed/36901829 http://dx.doi.org/10.3390/ijms24054393 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Rebolledo-Bustillo, Mariana
Garcia-Gomez, David
Dávila, Eliud Morales
Castro, María Eugenia
Caballero, Norma A.
Melendez, Francisco J.
Baizabal-Aguirre, Victor M.
Sanchez-Gaytan, Brenda L.
Perez-Aguilar, Jose Manuel
Structural Basis of the Binding Mode of the Antineoplastic Compound Motixafortide (BL-8040) in the CXCR4 Chemokine Receptor
title Structural Basis of the Binding Mode of the Antineoplastic Compound Motixafortide (BL-8040) in the CXCR4 Chemokine Receptor
title_full Structural Basis of the Binding Mode of the Antineoplastic Compound Motixafortide (BL-8040) in the CXCR4 Chemokine Receptor
title_fullStr Structural Basis of the Binding Mode of the Antineoplastic Compound Motixafortide (BL-8040) in the CXCR4 Chemokine Receptor
title_full_unstemmed Structural Basis of the Binding Mode of the Antineoplastic Compound Motixafortide (BL-8040) in the CXCR4 Chemokine Receptor
title_short Structural Basis of the Binding Mode of the Antineoplastic Compound Motixafortide (BL-8040) in the CXCR4 Chemokine Receptor
title_sort structural basis of the binding mode of the antineoplastic compound motixafortide (bl-8040) in the cxcr4 chemokine receptor
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10001991/
https://www.ncbi.nlm.nih.gov/pubmed/36901829
http://dx.doi.org/10.3390/ijms24054393
work_keys_str_mv AT rebolledobustillomariana structuralbasisofthebindingmodeoftheantineoplasticcompoundmotixafortidebl8040inthecxcr4chemokinereceptor
AT garciagomezdavid structuralbasisofthebindingmodeoftheantineoplasticcompoundmotixafortidebl8040inthecxcr4chemokinereceptor
AT davilaeliudmorales structuralbasisofthebindingmodeoftheantineoplasticcompoundmotixafortidebl8040inthecxcr4chemokinereceptor
AT castromariaeugenia structuralbasisofthebindingmodeoftheantineoplasticcompoundmotixafortidebl8040inthecxcr4chemokinereceptor
AT caballeronormaa structuralbasisofthebindingmodeoftheantineoplasticcompoundmotixafortidebl8040inthecxcr4chemokinereceptor
AT melendezfranciscoj structuralbasisofthebindingmodeoftheantineoplasticcompoundmotixafortidebl8040inthecxcr4chemokinereceptor
AT baizabalaguirrevictorm structuralbasisofthebindingmodeoftheantineoplasticcompoundmotixafortidebl8040inthecxcr4chemokinereceptor
AT sanchezgaytanbrendal structuralbasisofthebindingmodeoftheantineoplasticcompoundmotixafortidebl8040inthecxcr4chemokinereceptor
AT perezaguilarjosemanuel structuralbasisofthebindingmodeoftheantineoplasticcompoundmotixafortidebl8040inthecxcr4chemokinereceptor