Diversity of Bisubstrate Binding Modes of Adenosine Analogue–Oligoarginine Conjugates in Protein Kinase A and Implications for Protein Substrate Interactions

Conformational transition paths harbor structures useful for aiding drug discovery and understanding enzymatic mechanisms in protein kinases

“…Structures resembling the phosphate‐transfer step were found in this study of protein kinase A. For example, 3AGL and 3AGM depict the structures of two compounds, ARC‐1039 and ARC‐670, which are adducts of a peptide with an ATP analog. 3AGM was mined only by using the intermediate structure 21, not by the two end states, showing the extra information that a path simulation could provide beyond existing experimental structures.…”

“…The structures retrieved include those complexed with inhibitors, those with natural substrates such as ATP or peptide mimics bound, those with the regulatory subunit associated, and those with ligands intended to mimic the intermediate states in the enzymatic mechanism. Several structures: 1REK, 1STC, 3L9L, 1SZM, 3L9M, 4NTT, 3AGM, and 4C35 were only retrieved by the intermediate structures along the conformational transition path, not by the two end structures, the closed and the open forms derived from the experimental structures, indicating that the intermediate structures were quite different from the structures of the two end states.…”

Co-crystal structures of the protein kinase haspin with bisubstrate inhibitors

“…In (a) and (c) the amino-acid residues of haspin interacting with inhibitor are shown as sticks and are numbered; the hydrogen bonds are shown as dotted lines; a black circle shows the positioning of the C-terminus of the chiral spacer of the inhibitor and black arrows indicate the positioning of the side chain of the Lys residue corresponding to Lys(+1) in histone H3(1-7). the catalytic subunit of cAMP-dependent PK (Lavogina et al, 2009;Pflug et al, 2010). Another striking feature of the cocrystals of ARCs with haspin was the positioning of the aromatic side chain of Phe495: in both cases it was displaced from its previously reported folded position under the P-loop (Figs.…”

Cover Picture: Modulable and Highly Diastereoselective Carbometalations of Cyclopropenes (Chem. Eur. J. 4/2014)

“…According to the results of structure–affinity studies with generic ARC compounds and structural analysis of ARC/PKAc co‐crystals,19c ARCs can be tagged with voluminous groups at the C terminus of the peptide moiety without diminishing their affinity toward PKs. Here, a high‐affinity inhibitor ( 10 ) was labeled with the fluorescent dye PromoFluor‐647 via the side chain amino group of the lysine residue.…”

“…The dual binding mode of generic ARC‐type inhibitors with PKAc was firmly established through X‐ray analysis of ARC/PKAc co‐crystals and via displacement of ARC‐Fluo probes with single substrate‐competitive inhibitors 9c. 19 From the other side, the established sub‐micromolar affinity of a widely used transport peptide ( D ‐Arg) 9 ‐NH 2 toward Pim‐1 points to the possibility that the effect of the peptide on the properties of the cargo is not limited to increase of its cell uptake efficiency, but rather that protein phosphorylation balances could also be regulated by inhibition of Pim and other PKs by the transporter 20…”