3BWJ

Complex of PKA with the bisubstrate protein kinase inhibitor lead compound Arc-1034

Summary for 3BWJ

• Entry DOI: 10.2210/pdb3bwj/pdb
• Related PRD ID: PRD_000645
• Descriptor: cAMP-dependent protein kinase, alpha-catalytic subunit, (2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-N-(6-{[(1R)-4-carbamimidamido-1-{[(1R)-4-carbamimidamido-1-carbamoylbutyl]carbamoyl}butyl]amino}-6-oxohexyl)-3,4-dihydroxytetrahydrofuran-2-carboxamide (3 entities in total)
• Functional Keywords: bisubstrate inhibitor, protein kinase, serine/threonine-protein kinase, atp-binding, camp, phosphoprotein, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Bos taurus (bovine)
• Total number of polymer chains: 1
• Total formula weight: 42197.93

Authors

Lavogina, D.,Koenig, N.,Uri, A.,Bossemeyer, D. (deposition date: 2008-01-09, release date: 2009-02-03, Last modification date: 2019-09-04)

Primary citation

Lavogina, D.,Lust, M.,Viil, I.,Konig, N.,Raidaru, G.,Rogozina, J.,Enkvist, E.,Uri, A.,Bossemeyer, D.
Structural analysis of ARC-type inhibitor (ARC-1034) binding to protein kinase A catalytic subunit and rational design of bisubstrate analogue inhibitors of basophilic protein kinases.
J.Med.Chem., 52:308-321, 2009

PubMed Abstract: The crystal structure of a complex of the catalytic subunit (type alpha) of cAMP-dependent protein kinase (PKA C alpha) with ARC-type inhibitor (ARC-1034), the presumed lead scaffold of previously reported adenosine-oligo-arginine conjugate-based (ARC-type) inhibitors, was solved. Structural elements important for interaction with the kinase were established with specifically modified derivatives of the lead compound. On the basis of this knowledge, a new generation of inhibitors, conjugates of adenosine-4'-dehydroxymethyl-4'-carboxylic acid moiety and oligo(D-arginine), was developed with inhibitory constants well into the subnanomolar range. The structural determinants of selectivity of the new compounds were established in assays with ROCK-II and PKBgamma.

PubMed: 19143565
DOI: 10.1021/jm800797n

Experimental method

X-RAY DIFFRACTION (2.3 Å)