Structural analysis of platelet-derived growth factor receptor alpha by protein homology modeling

Constitutive phosphorylation activity by receptor tyrosine kinases due to activating mutations have been linked to human malignancies. Substitution mutation of tyrosine 849 to serine residue led to the constitutive phosphorylation of platelet-derived growth factor receptor alpha (PDGFRa) as found in...

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Main Author:	Hussin, Nurulfarhana
Format:	Thesis
Language:	English
Published:	2015
Subjects:	R Medicine (General)
Online Access:	http://eprints.utm.my/id/eprint/54058/25/NurulfarhanaHussinMFBME2015.pdf
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spelling	my-utm-ep.540582020-10-15T03:15:14Z Structural analysis of platelet-derived growth factor receptor alpha by protein homology modeling 2015-02 Hussin, Nurulfarhana R Medicine (General) Constitutive phosphorylation activity by receptor tyrosine kinases due to activating mutations have been linked to human malignancies. Substitution mutation of tyrosine 849 to serine residue led to the constitutive phosphorylation of platelet-derived growth factor receptor alpha (PDGFRa) as found in hypereosinophilic syndrome sample. An in silico study was conducted to identify whether PDGFRa catalytic domain can adopt an inactive conformation. The activating mutation Y849S was investigated to elucidate its role in destabilizing the inactive state of wild type PDGFRa catalytic domain. Three dimensional structure of PDGFRa catalytic domain in inactive conformation was modelled and refined with MD simulations using GROMOS96 force field with 53a6 parameter in GROMACS version 4.6.3. The model consists of juxtamembrane (JM) region and kinase domain. Presence of conserved tyrosine and tryptophan residues in JM region suggested its stabilizing role in inactive structure. Analysis of MD trajectories indicated that mutation Y849S at the C-terminal lobe had caused the loss of intramolecular hydrogen bondings which contributed to the increase of JM region fluctuations in the N-terminal lobe, higher hydrophilicity of activation loop (A-loop) that might loosen its packed conformation, and more solvent-exposed of JM region as a result of its reduced hydrophobicity. The shorter, non-aromatic side chain of serine residue at the position 849 is incapable to preserve the hydrogen bond network played by tyrosine residue in the wild type model. In conclusion, it is suggested, at least based on the model from this study that Y849 might play as stabilizing role in inactive conformation of PDGFRa catalytic domain by linking the inter-lobe interactions of A-loop and JM regions. Substitution of serine at the same position perturbs the interactions thus destabilize the inactive conformational state of the model. 2015-02 Thesis http://eprints.utm.my/id/eprint/54058/ http://eprints.utm.my/id/eprint/54058/25/NurulfarhanaHussinMFBME2015.pdf application/pdf en public http://dms.library.utm.my:8080/vital/access/manager/Repository/vital:86247 masters Universiti Teknologi Malaysia, Faculty of Biosciences and Medical Engineering Faculty of Biosciences and Medical Engineering
institution	Universiti Teknologi Malaysia
collection	UTM Institutional Repository
language	English
topic	R Medicine (General)
spellingShingle	R Medicine (General) Hussin, Nurulfarhana Structural analysis of platelet-derived growth factor receptor alpha by protein homology modeling
description	Constitutive phosphorylation activity by receptor tyrosine kinases due to activating mutations have been linked to human malignancies. Substitution mutation of tyrosine 849 to serine residue led to the constitutive phosphorylation of platelet-derived growth factor receptor alpha (PDGFRa) as found in hypereosinophilic syndrome sample. An in silico study was conducted to identify whether PDGFRa catalytic domain can adopt an inactive conformation. The activating mutation Y849S was investigated to elucidate its role in destabilizing the inactive state of wild type PDGFRa catalytic domain. Three dimensional structure of PDGFRa catalytic domain in inactive conformation was modelled and refined with MD simulations using GROMOS96 force field with 53a6 parameter in GROMACS version 4.6.3. The model consists of juxtamembrane (JM) region and kinase domain. Presence of conserved tyrosine and tryptophan residues in JM region suggested its stabilizing role in inactive structure. Analysis of MD trajectories indicated that mutation Y849S at the C-terminal lobe had caused the loss of intramolecular hydrogen bondings which contributed to the increase of JM region fluctuations in the N-terminal lobe, higher hydrophilicity of activation loop (A-loop) that might loosen its packed conformation, and more solvent-exposed of JM region as a result of its reduced hydrophobicity. The shorter, non-aromatic side chain of serine residue at the position 849 is incapable to preserve the hydrogen bond network played by tyrosine residue in the wild type model. In conclusion, it is suggested, at least based on the model from this study that Y849 might play as stabilizing role in inactive conformation of PDGFRa catalytic domain by linking the inter-lobe interactions of A-loop and JM regions. Substitution of serine at the same position perturbs the interactions thus destabilize the inactive conformational state of the model.
format	Thesis
qualification_level	Master's degree
author	Hussin, Nurulfarhana
author_facet	Hussin, Nurulfarhana
author_sort	Hussin, Nurulfarhana
title	Structural analysis of platelet-derived growth factor receptor alpha by protein homology modeling
title_short	Structural analysis of platelet-derived growth factor receptor alpha by protein homology modeling
title_full	Structural analysis of platelet-derived growth factor receptor alpha by protein homology modeling
title_fullStr	Structural analysis of platelet-derived growth factor receptor alpha by protein homology modeling
title_full_unstemmed	Structural analysis of platelet-derived growth factor receptor alpha by protein homology modeling
title_sort	structural analysis of platelet-derived growth factor receptor alpha by protein homology modeling
granting_institution	Universiti Teknologi Malaysia, Faculty of Biosciences and Medical Engineering
granting_department	Faculty of Biosciences and Medical Engineering
publishDate	2015
url	http://eprints.utm.my/id/eprint/54058/25/NurulfarhanaHussinMFBME2015.pdf
_version_	1747817675766104064

Structural analysis of platelet-derived growth factor receptor alpha by protein homology modeling

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