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Title
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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.
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Authors
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D.Lavogina,
M.Lust,
I.Viil,
N.König,
G.Raidaru,
J.Rogozina,
E.Enkvist,
A.Uri,
D.Bossemeyer.
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Ref.
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J Med Chem, 2009,
52,
308-321.
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PubMed id
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Abstract
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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.
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