Electrostatic Switch Function in the Mechanism of Protein Kinase A I Activation: Results of the Molecular Dynamics SimulationReportar como inadecuado




Electrostatic Switch Function in the Mechanism of Protein Kinase A I Activation: Results of the Molecular Dynamics Simulation - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

BioMed Research International - Volume 2017 2017, Article ID 5846073, 7 pages - https:-doi.org-10.1155-2017-5846073

Research Article

St. Petersburg State University, Universitetskaya nab. 7-9, St. Petersburg 199034, Russia

Pavlov Institute of Physiology, Russian Academy of Sciences, nab. Makarova 6, St. Petersburg 199034, Russia

Kyoto Sangyo University, Kamigamo-Motoyama, Kita-ku, Kyoto 603-8555, Japan

Correspondence should be addressed to Alexander A. Tokmakov and Vasiliy E. Stefanov

Received 6 November 2016; Revised 22 January 2017; Accepted 7 February 2017; Published 7 March 2017

Academic Editor: Serdar Kuyucak

Copyright © 2017 Olga N. Rogacheva et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

We used molecular dynamics to find the average path of the A-domain conformational transition in protein kinase A Iα. We obtained thirteen productive trajectories and processed them sequentially using factor and cross-correlation analyses. The conformational transition is presented as partly deterministic sequence of six events. Event B represents transition of the phosphate binding cassette. Main participants of this event form electrostatic switch cAMPO6–A202N-H–G199C=O. Through this switch, cAMP transmits information about its binding to hydrophobic switch L203–Y229 and thus triggers conformational transition of A-domain. Events C and D consist in N3A-motif displacement towards phosphate binding cassette and B-C-helix rotation. Event E involves an increase in interaction energy between Y229 and β-subdomain. Taken together, events B, E, and D correspond to the hinge movement towards β-barrel. Transition of B-C-helix turn a.a. 229–234 from α-form to π-form accounts for event F. Event G implies that π-helical turn is replaced by kink. Emerging in the resulting conformation, electrostatic interaction R241–E200 facilitates kink formation. The obtained data on the mechanism of cAMP-dependent activation of PKA Iα may contribute to new approaches to designing pharmaceuticals based on cAMP analogs.





Autor: Olga N. Rogacheva, Boris F. Shchegolev, Elena A. Vershinina, Alexander A. Tokmakov, and Vasiliy E. Stefanov

Fuente: https://www.hindawi.com/



DESCARGAR PDF




Documentos relacionados