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Understanding the molecular basis of EGFR kinase domain/MIG-6 peptide recognition complex using computational analyses
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Document Title
Understanding the molecular basis of EGFR kinase domain/MIG-6 peptide recognition complex using computational analyses
Author
Moonrin N.,Songtawee N.,Rattanabunyong S.,Chunsrivirot S.,Mokmak W.,Tongsima S.,Choowongkomon K.
Name from Authors Collection
Affiliations
Kasetsart University, Department of Biochemistry, Faculty of Science, 50 Ngam, Wong Wan Rd, Bangkok, Chatuchak, 10900, Thailand; Mahidol University, Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Bangkok, 10700, Thailand; Chulalongkorn University, Department of Biochemistry, Faculty of Science, Bangkok, Pathum Wan, 10330, Thailand; Kasetsart University, Genetic Engineering Interdisciplinary Program, Graduate School, 50 Ngam Wong Wan Rd, Bangkok, Chatuchak, 10900, Thailand; National Science and Technology Development Agency (NSTDA), Genome Technology Research Unit, National Center for Genetic Engineering and Biotechnology, 113 Thailand Science Park, Phahonyothin Road, Khlong Nueng, Pathum Thani, Khlong Luang, 12120, Thailand; University-Kasetsart University, Kasetsart University, Center for Advanced Studies in Tropical Natural Resources, National Research, Bangkok, Chatuchak, 10900, Thailand
Type
Article
Source Title
BMC Bioinformatics
ISSN
14712105
Year
2015
Volume
16
Issue
1
Open Access
All Open Access, Gold, Green
Publisher
BioMed Central Ltd.
DOI
10.1186/s12859-015-0528-x
Abstract
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. © Moonrin et al.
Keyword
cancer | EGFR | Inhibitor | MIG-6 segment1 | molecular dynamics simulations | Tyrosine kinase
Industrial Classification
Knowledge Taxonomy Level 1
Knowledge Taxonomy Level 2
Knowledge Taxonomy Level 3
Funding Sponsor
Chulalongkorn University; National Science and Technology Development Agency; Thailand Research Fund; Thailand Graduate Institute of Science and Technology
License
CC BY
Rights
Author
Publication Source
Scopus