Dynamics fingerprints of active conformers of epidermal growth factor receptor kinase. Issue 29 (9th October 2018)

• Record Type: Journal Article
• Authors: Barletta, German P.; Hasenahuer, Marcia Anahi; Fornasari, Maria Silvina; Parisi, Gustavo; Fernandez‐Alberti, Sebastian
• Is Part Of: Journal of computational chemistry. Volume 39:Issue 29(2018)
• Page Start: 2472
• Page End: 2480
• Publication Date: 2018-10-09
• Subjects: normal modes -- protein conformers -- Epidermal growth factor receptor -- dynamics fingerprints; Chemistry -- Data processing -- Periodicals; 542.85
• DOI: 10.1002/jcc.25590
• Languages: English
• ISSNs: 0192-8651

Abstract

Abstract : 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. Abstract : Mutations of Epidermal growth factor receptor (EGFR) have been associated to different human cancers altering the equilibrium of pre‐existing conformer populations, certain of which can become enzymatically more active than the wild‐type. A comparative analysis of dynamics features shared this active conformers. Two representative directions of motions have been found as dynamics fingerprints. Protein motion along both directions impacts on the cavity volume of the main pocket of the active site.