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Understanding the molecular basis of EGFR kinase domain/MIG-6 peptide recognition complex using computational analyses

BACKGROUND: Epidermal growth factor receptor (EGFR) signalling plays a major role in biological processes, including cell proliferation, differentiation and survival. Since the over-expression of EGFR causes human cancers, EGFR is an attractive drug target. A tumor suppressor endogenous protein, MIG...

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Autores principales: Moonrin, Ninnutt, Songtawee, Napat, Rattanabunyong, Siriluk, Chunsrivirot, Surasuk, Mokmak, Wanwimon, Tongsima, Sissades, Choowongkomon, Kiattawee
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383062/
https://www.ncbi.nlm.nih.gov/pubmed/25885222
http://dx.doi.org/10.1186/s12859-015-0528-x
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author Moonrin, Ninnutt
Songtawee, Napat
Rattanabunyong, Siriluk
Chunsrivirot, Surasuk
Mokmak, Wanwimon
Tongsima, Sissades
Choowongkomon, Kiattawee
author_facet Moonrin, Ninnutt
Songtawee, Napat
Rattanabunyong, Siriluk
Chunsrivirot, Surasuk
Mokmak, Wanwimon
Tongsima, Sissades
Choowongkomon, Kiattawee
author_sort Moonrin, Ninnutt
collection PubMed
description BACKGROUND: Epidermal growth factor receptor (EGFR) signalling plays a major role in biological processes, including cell proliferation, differentiation and survival. Since the over-expression of EGFR causes human cancers, EGFR is an attractive drug target. A tumor suppressor endogenous protein, MIG-6, is known to suppress EGFR over-expression by binding to the C-lobe of EGFR kinase. Thus, this C-lobe of the EGFR kinase is a potential new target for EGFR kinase activity inhibition. In this study, molecular dynamics (MD) simulations and binding free energy calculations were used to investigate the protein-peptide interactions between EGFR kinase and a 27-residue peptide derived from MIG-6_s1 segment (residues 336–362). RESULTS: These 27 residues of MIG-6_s1 were modeled from the published MIG-6 X-ray structure. The binding dynamics were detailed by applying the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method to predict the binding free energy. Both van der Waals interactions and non-polar solvation were favorable driving forces for binding process. Six residues of EGFR kinase and eight residues of MIG-6_s1 residues were shown to be responsible for interface binding in which we investigated per residue free energy decomposition and the results from the computational alanine scanning approach. These residues also had higher hydrogen bond occupancies than other residues at the binding interface. The results from the aforementioned calculations reasonably agreed with the previous experimental mutagenesis studies. CONCLUSIONS: Molecular dynamics simulations were used to investigate the interactions of MIG-6_s1 to EGFR kinase domain. Our study provides an insight into such interactions that is useful in guiding the design of novel anticancer therapeutics. The information on our modelled peptide interface with EGFR kinase could be a possible candidate for an EGFR dimerization inhibitor.
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spelling pubmed-43830622015-04-03 Understanding the molecular basis of EGFR kinase domain/MIG-6 peptide recognition complex using computational analyses Moonrin, Ninnutt Songtawee, Napat Rattanabunyong, Siriluk Chunsrivirot, Surasuk Mokmak, Wanwimon Tongsima, Sissades Choowongkomon, Kiattawee BMC Bioinformatics Research Article BACKGROUND: Epidermal growth factor receptor (EGFR) signalling plays a major role in biological processes, including cell proliferation, differentiation and survival. Since the over-expression of EGFR causes human cancers, EGFR is an attractive drug target. A tumor suppressor endogenous protein, MIG-6, is known to suppress EGFR over-expression by binding to the C-lobe of EGFR kinase. Thus, this C-lobe of the EGFR kinase is a potential new target for EGFR kinase activity inhibition. In this study, molecular dynamics (MD) simulations and binding free energy calculations were used to investigate the protein-peptide interactions between EGFR kinase and a 27-residue peptide derived from MIG-6_s1 segment (residues 336–362). RESULTS: These 27 residues of MIG-6_s1 were modeled from the published MIG-6 X-ray structure. The binding dynamics were detailed by applying the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method to predict the binding free energy. Both van der Waals interactions and non-polar solvation were favorable driving forces for binding process. Six residues of EGFR kinase and eight residues of MIG-6_s1 residues were shown to be responsible for interface binding in which we investigated per residue free energy decomposition and the results from the computational alanine scanning approach. These residues also had higher hydrogen bond occupancies than other residues at the binding interface. The results from the aforementioned calculations reasonably agreed with the previous experimental mutagenesis studies. CONCLUSIONS: Molecular dynamics simulations were used to investigate the interactions of MIG-6_s1 to EGFR kinase domain. Our study provides an insight into such interactions that is useful in guiding the design of novel anticancer therapeutics. The information on our modelled peptide interface with EGFR kinase could be a possible candidate for an EGFR dimerization inhibitor. BioMed Central 2015-03-27 /pmc/articles/PMC4383062/ /pubmed/25885222 http://dx.doi.org/10.1186/s12859-015-0528-x Text en © Moonrin et al.; licensee BioMed Central. 2015 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Moonrin, Ninnutt
Songtawee, Napat
Rattanabunyong, Siriluk
Chunsrivirot, Surasuk
Mokmak, Wanwimon
Tongsima, Sissades
Choowongkomon, Kiattawee
Understanding the molecular basis of EGFR kinase domain/MIG-6 peptide recognition complex using computational analyses
title Understanding the molecular basis of EGFR kinase domain/MIG-6 peptide recognition complex using computational analyses
title_full Understanding the molecular basis of EGFR kinase domain/MIG-6 peptide recognition complex using computational analyses
title_fullStr Understanding the molecular basis of EGFR kinase domain/MIG-6 peptide recognition complex using computational analyses
title_full_unstemmed Understanding the molecular basis of EGFR kinase domain/MIG-6 peptide recognition complex using computational analyses
title_short Understanding the molecular basis of EGFR kinase domain/MIG-6 peptide recognition complex using computational analyses
title_sort understanding the molecular basis of egfr kinase domain/mig-6 peptide recognition complex using computational analyses
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383062/
https://www.ncbi.nlm.nih.gov/pubmed/25885222
http://dx.doi.org/10.1186/s12859-015-0528-x
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