title: Mechanisms of PDGFRalpha promiscuity and PDGFRbeta specificity in association with PDGFB.
abstract: Platelet-derived growth factor receptor alpha (PDGFRalpha) interacts with PDGFs A, B, C and AB, while PDGFRbeta binds to PDGFs B and D, thus suggesting that PDGFRalpha is more promiscuous than PDGFRbeta. The structural analysis of PDGFRalpha-PDGFA and PDGFRalpha-PDGFB complexes and a molecular explanation for the promiscuity of PDGFRalpha and the specificity of PDGFRbeta remain unclear. In the present study, we modeled the three extracellular domains of PDGFRalpha using a previous crystallographic structure of PDGFRbeta as a template. Additionally, we analyzed the interacting residues of PDGFRalpha-PDGFA and PDGFRalpha-PDGFB complexes using docking simulations. The validation of the resulting complexes was evaluated by molecular dynamics simulations. Structural analysis revealed that changes of non-aromatic amino acids in PDGFRalpha to aromatic amino acids in PDGFRbeta (I139F, P267F and N204Y) may be involved in the promiscuity of PDGFRalpha. Indeed, substitution of amino acids with few probabilities of rotamer changes in PDGFRbeta (M133A, N163E and N179S) and energy stability due to the formation of hydrogen bond in PDGFRbeta could explain the specificity of PDGFRbeta. These results may be used as an input for a better and more specific drug and peptide design targeting diseases related with the malfunction of PDGFs and PDGFRalpha such as cancer and atherosclerosis.
authors.affiliation: fbs.
authors.forename: Daniel
authors.initials: D
authors.lastname: Torrente
authors.affiliation: fbs.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Cabezas
authors.affiliation: fbs.
authors.forename: Marcos
authors.initials: M
authors.lastname: Avila
authors.affiliation: fbs.
authors.forename: Yuly
authors.initials: Y
authors.lastname: Sanchez
authors.affiliation: fbs.
authors.forename: Ludis
authors.initials: L
authors.lastname: Morales
authors.affiliation: King Fahd Medical Research Center, King Abdulaziz University, P.O. Box 80216, Jeddah 21589, Saudi Arabia.
authors.forename: Ghulam Md
authors.initials: GM
authors.lastname: Ashraf
authors.affiliation: fbs.
authors.forename: George E
authors.initials: GE
authors.lastname: Barreto
authors.affiliation: Departamento de Nutricion y Bioquimica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogota D.C., Colombia. Carrera 7ª # 43-82, Carlos Ortiz Bldg, S. J.; Lab. 107/108, gonzalez@javeriana.edu.co.
authors.forename: Janneth
authors.initials: J
authors.lastname: Gonzalez
authors.affiliation: GALLY International Biomedical Research Consulting LLC., 7733 Louis Pasteur Drive, #330, San Antonio, TX, USA 78229, AND School of Health Science and Healthcare Administration, University of Atlanta, E. Johns Crossing, #175, Johns Creek, GA, USA 30097.
authors.forename: Gjumrackh
authors.initials: G
authors.lastname: Aliev
mesh_terms: D001665:Binding Sites; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000737:chemistry* / Q000378:metabolism; D016415:Sequence Alignment; D020539:Sequence Analysis, Protein; D015398:Signal Transduction
chemical_list: D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta