Electrostatic Switch Function in the Mechanism of Protein Kinase A i α Activation

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Electrostatic Switch Function in the Mechanism of Protein Kinase A i α Activation : Results of the Molecular Dynamics Simulation. / Rogacheva, Olga N.; Shchegolev, Boris F.; Vershinina, Elena A.; Tokmakov, Alexander A.; Stefanov, Vasiliy E.

In: BioMed Research International, Vol. 2017, No. 1-8, 5846073, 2017.

Research output: Contribution to journal › Article › peer-review

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@article{64ba24508a424f8cb60de423779771e8,

title = "Electrostatic Switch Function in the Mechanism of Protein Kinase A i α Activation: 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 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.",

author = "Rogacheva, {Olga N.} and Shchegolev, {Boris F.} and Vershinina, {Elena A.} and Tokmakov, {Alexander A.} and Stefanov, {Vasiliy E.}",

year = "2017",

doi = "10.1155/2017/5846073",

language = "English",

volume = "2017",

journal = "BioMed Research International",

issn = "2314-6133",

publisher = "Hindawi ",

number = "1-8",

}

RIS

TY - JOUR

T1 - Electrostatic Switch Function in the Mechanism of Protein Kinase A i α Activation

T2 - Results of the Molecular Dynamics Simulation

AU - Rogacheva, Olga N.

AU - Shchegolev, Boris F.

AU - Vershinina, Elena A.

AU - Tokmakov, Alexander A.

AU - Stefanov, Vasiliy E.

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85015912492&partnerID=8YFLogxK

U2 - 10.1155/2017/5846073

DO - 10.1155/2017/5846073

M3 - Article

C2 - 28367443

VL - 2017

JO - BioMed Research International

JF - BioMed Research International

SN - 2314-6133

IS - 1-8

M1 - 5846073

ER -

ID: 7739691

Electrostatic Switch Function in the Mechanism of Protein Kinase A i α Activation: Results of the Molecular Dynamics Simulation

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