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Mechanisms of PDGFRalpha promiscuity and PDGFRbeta specificity in association with PDGFB
Daniel Torrente1,Ricardo Cabezas1,Marcos Avila1,Yuly Sanchez1,Ludis Morales1,Ghulam Md Ashraf2,George E. Barreto1,Janneth Gonzalez1,*,Gjumrakch Aliev3,4
1
Departamento de Nutricion y Bioquimica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogota D.C., Colombia. Carrera 7ª # 43-82, Carlos Ortiz Bldg, S. J.
2
King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah, Saudi Arabia 21589
3
GALLY International Biomedical Research Consulting LLC., 7733 Louis Pasteur Drive, #330, San Antonio, TX, USA 78229
4
School of Health Science and Healthcare Administration, University of Atlanta, E. Johns Crossing, #175, Johns Creek, GA, USA 30097
DOI: 10.2741/E741 Volume 7 Issue 3, pp.434-446
Published: 01 June 2015
(This article belongs to the Special Issue Type II transmembrane serine proteases)
*Corresponding Author(s):  
Janneth Gonzalez
E-mail:  
janneth.gonzalez@javeriana.edu.co
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. Our results show that 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. These results may be used as an input for a better peptide design targeting diseases related with the malfunction of PDGF system such as cancer and atherosclerosis.

Key words
PDGFRbeta,PDGFRalpha,Molecular Modeling,Promiscuity,Specificity
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Daniel Torrente, Ricardo Cabezas, Marcos Avila, Yuly Sanchez, Ludis Morales, Ghulam Md Ashraf, George E. Barreto, Janneth Gonzalez, Gjumrakch Aliev. Mechanisms of PDGFRalpha promiscuity and PDGFRbeta specificity in association with PDGFB. Frontiers in Bioscience-Elite. 2015. 7(3); 434-446.