Structural signature of the G719S-T790M double mutation in the EGFR kinase domain and its response to inhibitors

George Priya Doss C.; Rajith B.; Chiranjib Chakraborty; NagaSundaram N.; Shabana Kouser Ali; Hailong Zhu

doi:10.1038/srep05868

Structural signature of the G719S-T790M double mutation in the EGFR kinase domain and its response to inhibitors

George Priya Doss C.^*, Rajith B., Chiranjib Chakraborty, NagaSundaram N., Shabana Kouser Ali, Hailong Zhu^*

^*Corresponding author for this work

Department of Computer Science

Research output: Contribution to journal › Journal article › peer-review

43 Citations (Scopus)

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 (50â €..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.

Original language	English
Article number	5868
Number of pages	7
Journal	Scientific Reports
Volume	4
DOIs	https://doi.org/10.1038/srep05868
Publication status	Published - 5 Aug 2014

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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{\^a} €..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.",

author = "C., {George Priya Doss} and Rajith B. and Chiranjib Chakraborty and NagaSundaram N. and Ali, {Shabana Kouser} and Hailong Zhu",

note = "Funding Information: This work was supported by the Research Grants Council of Hong Kong [212111], [212613] and Faculty Research Grant of Hong Kong Baptist University [FRG2/12-13/061]. The authors take this opportunity to thank the management of VIT and Galgotias University for providing the facilities and encouragement to carry out this work. Publisher copyright: {\textcopyright} 2014, The Author(s) ",

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doi = "10.1038/srep05868",

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AU - N., NagaSundaram

AU - Ali, Shabana Kouser

AU - Zhu, Hailong

N1 - Funding Information: This work was supported by the Research Grants Council of Hong Kong [212111], [212613] and Faculty Research Grant of Hong Kong Baptist University [FRG2/12-13/061]. The authors take this opportunity to thank the management of VIT and Galgotias University for providing the facilities and encouragement to carry out this work. Publisher copyright: © 2014, The Author(s)

PY - 2014/8/5

Y1 - 2014/8/5

N2 - 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 (50â €..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.

AB - 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 (50â €..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.

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Structural signature of the G719S-T790M double mutation in the EGFR kinase domain and its response to inhibitors

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