title: Structural signature of the G719S-T790M double mutation in the EGFR kinase domain and its response to inhibitors.
abstract: Some individuals with non-small-cell lung cancer (NSCLC) benefit from therapies targeting epidermal growth factor receptor (EGFR), and the characterization of a new mechanism of resistance to the EGFR-specific antibody gefitinib will provide valuable insight into how therapeutic strategies might be designed to overcome this particular resistance mechanism. The G719S and T790M mutations and their combination were involved in causing different conformational redistribution of EGFR. In the present computational study, we analyzed the impact and structural influence of G719S/T790M double mutation (DM) in EGFR with ligand (gefitinib) through molecular dynamic simulation (50 ns) and docking analysis. We observed the escalation in distance between the functional loop and activation loop with respect to T790M mutation compared to the G719S mutation. Furthermore, we confirmed that the G719S mutation causes the ligand to move closer to the hinge region, whereas T790M makes the ligand escape from the binding pocket. Obtained results provide with an explanation for the resistance induced by T790M and a vital clue for the design of drugs to combat gefitinib resistance.
authors.affiliation: Medical Biotechnology Division, School of Biosciences and Technology, VIT University, Vellore, Tamil Nadu, India.
authors.forename: George Priya C
authors.initials: GP
authors.lastname: Doss
authors.affiliation: Medical Biotechnology Division, School of Biosciences and Technology, VIT University, Vellore, Tamil Nadu, India.
authors.forename: B
authors.initials: B
authors.lastname: Rajith
authors.affiliation: Department of Bio-informatics, School of Computer and Information Sciences, Galgotias University, India.
authors.forename: Chiranjib
authors.initials: C
authors.lastname: Chakraborty
authors.affiliation: Medical Biotechnology Division, School of Biosciences and Technology, VIT University, Vellore, Tamil Nadu, India.
authors.forename: N
authors.initials: N
authors.lastname: NagaSundaram
authors.affiliation: Medical Biotechnology Division, School of Biosciences and Technology, VIT University, Vellore, Tamil Nadu, India.
authors.forename: Shabana Kouser
authors.initials: SK
authors.lastname: Ali
authors.affiliation: Department of Computer Science, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
authors.forename: Hailong
authors.initials: H
authors.lastname: Zhu
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000077156:Gefitinib; D015870:Gene Expression; D006801:Humans; D008024:Ligands; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009154:Mutation; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D025341:Principal Component Analysis; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011799:Quinazolines / Q000737:chemistry* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2070-5
references.pmid: 18227510
references.citation: Semin Oncol. 2002 Oct;29(5 Suppl 14):3-9
references.pmid: 12422308
references.citation: Nat Rev Mol Cell Biol. 2001 Feb;2(2):127-37
references.pmid: 11252954
references.citation: Acta Crystallogr D Biol Crystallogr. 2004 Aug;60(Pt 8):1355-63
references.pmid: 15272157
references.citation: Proteins. 1993 Dec;17(4):412-25
references.pmid: 8108382
references.citation: Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13306-11
references.pmid: 15329413
references.citation: Oncogene. 2013 Jan 3;32(1):27-38
references.pmid: 22349823
references.citation: Mol Cancer Ther. 2009 Aug;8(8):2142-51
references.pmid: 19671738
references.citation: Biopolymers. 1983 Dec;22(12):2577-637
references.pmid: 6667333
references.citation: Nat Chem Biol. 2007 Nov;3(11):722-6
references.pmid: 17922005
references.citation: Int J Cancer. 2006 Jan 15;118(2):257-62
references.pmid: 16231326
references.citation: N Engl J Med. 2004 May 20;350(21):2129-39
references.pmid: 15118073
references.citation: Proteins. 2006 Jul 1;64(1):210-8
references.pmid: 16617427
references.citation: Cancer Res. 2002 Oct 15;62(20):5749-54
references.pmid: 12384534
references.citation: PLoS One. 2012;7(2):e32131
references.pmid: 22384157
references.citation: Science. 2001 Aug 3;293(5531):876-80
references.pmid: 11423618
references.citation: Nucleic Acids Res. 2010 Jul;38(Web Server issue):W569-75
references.pmid: 20462859
references.citation: N Engl J Med. 2005 Feb 24;352(8):786-92
references.pmid: 15728811
references.citation: PLoS Comput Biol. 2011 Oct;7(10):e1002179
references.pmid: 21998569
references.citation: Hum Mutat. 2012 Nov;33(11):1566-75
references.pmid: 22753356
references.citation: J Am Chem Soc. 2006 Oct 18;128(41):13435-41
references.pmid: 17031956
references.citation: Proteins. 2013 May;81(5):852-62
references.pmid: 23255146