Electrostatic Switch Function in the Mechanism of Protein Kinase A Iα Activation: Results of the Molecular Dynamics Simulation
We used molecular dynamics to find the average path of the A-domain H→B 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 det...
Main Authors: | , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Hindawi Limited
2017-01-01
|
Series: | BioMed Research International |
Online Access: | http://dx.doi.org/10.1155/2017/5846073 |
id |
doaj-ea681715ab3b489bb95f4187905a986b |
---|---|
record_format |
Article |
spelling |
doaj-ea681715ab3b489bb95f4187905a986b2020-11-24T22:33:49ZengHindawi LimitedBioMed Research International2314-61332314-61412017-01-01201710.1155/2017/58460735846073Electrostatic Switch Function in the Mechanism of Protein Kinase A Iα Activation: Results of the Molecular Dynamics SimulationOlga N. Rogacheva0Boris F. Shchegolev1Elena A. Vershinina2Alexander A. Tokmakov3Vasiliy E. Stefanov4St. Petersburg State University, Universitetskaya nab. 7/9, St. Petersburg 199034, RussiaPavlov Institute of Physiology, Russian Academy of Sciences, nab. Makarova 6, St. Petersburg 199034, RussiaPavlov Institute of Physiology, Russian Academy of Sciences, nab. Makarova 6, St. Petersburg 199034, RussiaKyoto Sangyo University, Kamigamo-Motoyama, Kita-ku, Kyoto 603-8555, JapanSt. Petersburg State University, Universitetskaya nab. 7/9, St. Petersburg 199034, RussiaWe used molecular dynamics to find the average path of the A-domain H→B 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 H→B transition of the phosphate binding cassette. Main participants of this event form electrostatic switch cAMP(O6)–A202(N-H)–G199(C=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.http://dx.doi.org/10.1155/2017/5846073 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Olga N. Rogacheva Boris F. Shchegolev Elena A. Vershinina Alexander A. Tokmakov Vasiliy E. Stefanov |
spellingShingle |
Olga N. Rogacheva Boris F. Shchegolev Elena A. Vershinina Alexander A. Tokmakov Vasiliy E. Stefanov Electrostatic Switch Function in the Mechanism of Protein Kinase A Iα Activation: Results of the Molecular Dynamics Simulation BioMed Research International |
author_facet |
Olga N. Rogacheva Boris F. Shchegolev Elena A. Vershinina Alexander A. Tokmakov Vasiliy E. Stefanov |
author_sort |
Olga N. Rogacheva |
title |
Electrostatic Switch Function in the Mechanism of Protein Kinase A Iα Activation: Results of the Molecular Dynamics Simulation |
title_short |
Electrostatic Switch Function in the Mechanism of Protein Kinase A Iα Activation: Results of the Molecular Dynamics Simulation |
title_full |
Electrostatic Switch Function in the Mechanism of Protein Kinase A Iα Activation: Results of the Molecular Dynamics Simulation |
title_fullStr |
Electrostatic Switch Function in the Mechanism of Protein Kinase A Iα Activation: Results of the Molecular Dynamics Simulation |
title_full_unstemmed |
Electrostatic Switch Function in the Mechanism of Protein Kinase A Iα Activation: Results of the Molecular Dynamics Simulation |
title_sort |
electrostatic switch function in the mechanism of protein kinase a iα activation: results of the molecular dynamics simulation |
publisher |
Hindawi Limited |
series |
BioMed Research International |
issn |
2314-6133 2314-6141 |
publishDate |
2017-01-01 |
description |
We used molecular dynamics to find the average path of the A-domain H→B 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 H→B transition of the phosphate binding cassette. Main participants of this event form electrostatic switch cAMP(O6)–A202(N-H)–G199(C=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. |
url |
http://dx.doi.org/10.1155/2017/5846073 |
work_keys_str_mv |
AT olganrogacheva electrostaticswitchfunctioninthemechanismofproteinkinaseaiaactivationresultsofthemoleculardynamicssimulation AT borisfshchegolev electrostaticswitchfunctioninthemechanismofproteinkinaseaiaactivationresultsofthemoleculardynamicssimulation AT elenaavershinina electrostaticswitchfunctioninthemechanismofproteinkinaseaiaactivationresultsofthemoleculardynamicssimulation AT alexanderatokmakov electrostaticswitchfunctioninthemechanismofproteinkinaseaiaactivationresultsofthemoleculardynamicssimulation AT vasiliyestefanov electrostaticswitchfunctioninthemechanismofproteinkinaseaiaactivationresultsofthemoleculardynamicssimulation |
_version_ |
1725729227194499072 |