Dynamics fingerprints of active conformers of epidermal growth factor receptor kinase.

Autor: Barletta GP; Departamento de Ciencia y Tecnologia, Universidad Nacional de Quilmes/CONICET, Roque Saenz Peña 352, B1876BXD, Bernal, Argentina., Hasenahuer MA; Departamento de Ciencia y Tecnologia, Universidad Nacional de Quilmes/CONICET, Roque Saenz Peña 352, B1876BXD, Bernal, Argentina., Fornasari MS; Departamento de Ciencia y Tecnologia, Universidad Nacional de Quilmes/CONICET, Roque Saenz Peña 352, B1876BXD, Bernal, Argentina., Parisi G; Departamento de Ciencia y Tecnologia, Universidad Nacional de Quilmes/CONICET, Roque Saenz Peña 352, B1876BXD, Bernal, Argentina., Fernandez-Alberti S; Departamento de Ciencia y Tecnologia, Universidad Nacional de Quilmes/CONICET, Roque Saenz Peña 352, B1876BXD, Bernal, Argentina.
Jazyk: angličtina
Zdroj: Journal of computational chemistry [J Comput Chem] 2018 Nov 05; Vol. 39 (29), pp. 2472-2480. Date of Electronic Publication: 2018 Oct 09.
DOI: 10.1002/jcc.25590
Abstrakt: Epidermal growth factor receptor (EGFR) is a prototypical cell-surface receptor that plays a key role in the regulation of cellular signaling, proliferation and differentiation. Mutations of its kinase domain have been associated with the development of a variety of cancers and, therefore, it has been the target of drug design. Single amino acid substitutions (SASs) in this domain have been proven to alter the equilibrium of pre-existing conformer populations. Despite the advances in structural descriptions of its so-called active and inactive conformations, the associated dynamics aspects that characterize them have not been thoroughly studied yet. As the dynamic behaviors and molecular motions of proteins are important for a complete understanding of their structure-function relationships we present a novel procedure, using (or based on) normal mode analysis, to identify the collective dynamics shared among different conformers in EGFR kinase. The method allows the comparison of patterns of low-frequency vibrational modes defining representative directions of motions. Our procedure is able to emphasize the main similarities and differences between the collective dynamics of different conformers. In the case of EGFR kinase, two representative directions of motions have been found as dynamics fingerprints of the active conformers. Protein motion along both directions reveals to have a significant impact on the cavity volume of the main pocket of the active site. Otherwise, the inactive conformers exhibit a more heterogeneous distribution of collective motions. © 2018 Wiley Periodicals, Inc.
(© 2018 Wiley Periodicals, Inc.)
Databáze: MEDLINE
Externí odkaz: