title: Electrostatic Switch Function in the Mechanism of Protein Kinase A IαActivation: Results of the Molecular Dynamics Simulation.
abstract: 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 andβ-subdomain. Taken together, events B, E, and D correspond to the hinge movement towardsβ-barrel. Transition of B/C-helix turn (a.a. 229-234) fromα-form toπ-form accounts for event F. Event G implies thatπ-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 Iαmay contribute to new approaches to designing pharmaceuticals based on cAMP analogs.
authors.affiliation: St. Petersburg State University, Universitetskaya nab. 7/9, St. Petersburg 199034, Russia.
authors.forename: Olga N
authors.initials: ON
authors.lastname: Rogacheva
authors.affiliation: Pavlov Institute of Physiology, Russian Academy of Sciences, nab. Makarova 6, St. Petersburg 199034, Russia.
authors.forename: Boris F
authors.initials: BF
authors.lastname: Shchegolev
authors.affiliation: Pavlov Institute of Physiology, Russian Academy of Sciences, nab. Makarova 6, St. Petersburg 199034, Russia.
authors.forename: Elena A
authors.identifier: 0000-0002-8873-4409
authors.initials: EA
authors.lastname: Vershinina
authors.affiliation: Kyoto Sangyo University, Kamigamo-Motoyama, Kita-ku, Kyoto 603-8555, Japan.
authors.forename: Alexander A
authors.identifier: 0000-0003-2455-1184
authors.initials: AA
authors.lastname: Tokmakov
authors.affiliation: St. Petersburg State University, Universitetskaya nab. 7/9, St. Petersburg 199034, Russia.
authors.forename: Vasiliy E
authors.identifier: 0000-0002-7407-8236
authors.initials: VE
authors.lastname: Stefanov
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D000242:Cyclic AMP / Q000737:chemistry* / Q000627:therapeutic use; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation / Q000187:drug effects; D000072417:Protein Domains; D055672:Static Electricity
chemical_list: D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases