Initiation of the 3':5'-AMP-induced protein kinase A Iα regulatory subunit conformational transition. Part I. A202 and A326 are critical residues.
Protein-ligand docking and molecular dynamics studies have shown that the key event initiated by 3':5'-AMP binding to the A- and B-domains of protein kinase A Iα regulatory subunit is formation of a hydrogen bond between 3':5'-AMP and A202(A326) (the residue in parentheses being from the B-domain). The A202(A326) amide group movement associated with the bond formation leads to reorganization of the phosphate binding cassette (PBC) (the short 3(10)-helix becomes the long α-helix). This process results in L203(L327) displacement and finally causes hinge (B-helix) rotation. The L203(L327) displacement and packing into the hydrophobic pocket formed by the PBC and β2β3-loop also depends on the β2β3-loop conformation. The correct conformation is maintained by R, I, E, but not K at position 209(333) of the A- and B-domains. So, the R209K and R333K mutants have problems with reaching B-conformation. The apo-form of the 3':5'-AMP-binding domain also undergoes transition from H- to B-conformation. In this case, the movement of A202(A326) amide group seems to be a result of reorganization of the PBC into a more stable α-helix.
St. Petersburg State University, Universitetskaya nab. 7/9, 199034 St. Petersburg, Russia. AcerLaetum@yandex.ru
O N
ON
Rogacheva
B F
BF
Shchegolev
V E
VE
Stefanov
G A
GA
Zakharov
E V
EV
Savvateeva-Popova
D001665:Binding Sites; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000378:metabolism; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D056004:Molecular Dynamics Simulation; D009154:Mutation; D010710:Phosphates / Q000737:chemistry / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013816:Thermodynamics
D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D008024:Ligands; D010710:Phosphates; D000242:Cyclic AMP