Initiation of the 3′:5′-AMP-Induced Protein Kinase A Iα Regulatory Subunit Conformational Transition. Part II. Inhibition by Rp-3′:5′-AMPS

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O. N. Rogacheva^1*, B. F. Shchegolev², V. E. Stefanov¹, and E. V. Savvateeva-Popova²

¹St. Petersburg State University, Universitetskaya nab. 7/9, 199034 St. Petersburg, Russia; fax: (812) 328-9703; E-mail: AcerLaetum@yandex.ru

²Pavlov Institute of Physiology, Russian Academy of Sciences, nab. Makarova 6, 199034 St. Petersburg, Russia

^* To whom correspondence should be addressed.

Received January 12, 2012

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Protein–ligand docking and ab initio calculations have shown that the 3′:5′-AMP phosphorothioate analog (Rp-3′:5′-AMPS) blocks the A326 amide group displacement typical of transition from the H- to B-conformation within the B-domain of protein kinase A Iα R-subunit. This behavior of Rp-3′:5′-AMPS leads to the inhibition of initial stages of hydrophobic relay operation. In accordance with the proposed hypothesis, Rp-3′:5′-AMPS similarly to 3′:5′-AMP forms a hydrogen bond with the amide group of A326; however, the properties of this bond together with the position of the sulfur atom prevent the movement of A326. Finally, the Rp-3′:5′-AMPS-bound domain appears to be locked in the H-conformation, which is in agreement with the X-ray data.

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KEY WORDS: B-domain of PKA Iα R-subunit, 3′:5′-AMP, Rp-3′:5′-AMPS, A326, protein–ligand docking, quantum chemical analysis

DOI: 10.1134/S0006297912050069

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