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