The discovery of mutations within the kinase domain of the epidermal growth factor receptor (EGFR) gene has enabled a new era of targeted therapy in non-small cell lung cancer (NSCLC). Drugs belonging to the family of tyrosine kinase inhibitors (TKIs) are designed to bind ATP binding cleft, anyway, the occurrence of aminoacidic mutations decreases the effectiveness of the antitumoral treatment. Despite many efforts has been already made, the impact of the mutations on conformation and stability of EGFR-ATP complexes is still not fully understood. Therefore, we investigated the effect of mutations that leads to changes in Michaelis-Menten constant (Km) using dynamic docking simulations. We focused on six different EGFR forms in relation to different mutation states, then we found a good correlation between the calculated ATP affinities and Km values. Moreover, since dynamic switching of TKEGFR from the inactive towards the active state is known to regulate the kinase activity, we observed that ATP induces the inwards movement of the aC-helix with the Lys745 close to Glu762 in all cases. This means that ATP binding should be the first step in promoting the conformational shift to the active state. Finally, we highlighted for the first time the key contribution of water hydrogen bond and water-bridge networks in the modulation of ATP affinity. The identified mutant-specific ATP binding patterns and conformational features could be much useful to guide cancer therapy and develop more personalized medicine.

Mechanistic insight toward EGFR activation induced by ATP: role of mutations and water in ATP binding patterns / Laudadio, Emiliano; Mobbili, Giovanna; Sorci, Leonardo; Galeazzi, Roberta; Minnelli, Cristina. - In: JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS. - ISSN 0739-1102. - ELETTRONICO. - (2022), pp. 1-10. [10.1080/07391102.2022.2108497]

Mechanistic insight toward EGFR activation induced by ATP: role of mutations and water in ATP binding patterns

Emiliano Laudadio
Primo
;
Giovanna Mobbili;Leonardo Sorci;Roberta Galeazzi
;
Cristina Minnelli
2022-01-01

Abstract

The discovery of mutations within the kinase domain of the epidermal growth factor receptor (EGFR) gene has enabled a new era of targeted therapy in non-small cell lung cancer (NSCLC). Drugs belonging to the family of tyrosine kinase inhibitors (TKIs) are designed to bind ATP binding cleft, anyway, the occurrence of aminoacidic mutations decreases the effectiveness of the antitumoral treatment. Despite many efforts has been already made, the impact of the mutations on conformation and stability of EGFR-ATP complexes is still not fully understood. Therefore, we investigated the effect of mutations that leads to changes in Michaelis-Menten constant (Km) using dynamic docking simulations. We focused on six different EGFR forms in relation to different mutation states, then we found a good correlation between the calculated ATP affinities and Km values. Moreover, since dynamic switching of TKEGFR from the inactive towards the active state is known to regulate the kinase activity, we observed that ATP induces the inwards movement of the aC-helix with the Lys745 close to Glu762 in all cases. This means that ATP binding should be the first step in promoting the conformational shift to the active state. Finally, we highlighted for the first time the key contribution of water hydrogen bond and water-bridge networks in the modulation of ATP affinity. The identified mutant-specific ATP binding patterns and conformational features could be much useful to guide cancer therapy and develop more personalized medicine.
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11566/306582
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? 2
  • Scopus 7
  • ???jsp.display-item.citation.isi??? 7
social impact