title: 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.
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.
authors.affiliation: Institute of Chemistry, 2 Jakobi Street, 51014 Tartu, Estonia.
authors.forename: Darja
authors.initials: D
authors.lastname: Lavogina
authors.forename: Marje
authors.initials: M
authors.lastname: Lust
authors.forename: Indrek
authors.initials: I
authors.lastname: Viil
authors.forename: Norbert
authors.initials: N
authors.lastname: König
authors.forename: Gerda
authors.initials: G
authors.lastname: Raidaru
authors.forename: Jevgenia
authors.initials: J
authors.lastname: Rogozina
authors.forename: Erki
authors.initials: E
authors.lastname: Enkvist
authors.forename: Asko
authors.initials: A
authors.lastname: Uri
authors.forename: Dirk
authors.initials: D
authors.lastname: Bossemeyer
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D001491:Basophils / Q000201:enzymology*; D020134:Catalytic Domain; D002417:Cattle; D003461:Crystallography; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D004151:Dipeptides / Q000737:chemistry* / Q000494:pharmacology; D005454:Fluorescence Polarization; D008958:Models, Molecular; D008969:Molecular Sequence Data; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D017386:Sequence Homology, Amino Acid
chemical_list: C535236:ARC 1034; D004151:Dipeptides; D047428:Protein Kinase Inhibitors; D017868:Cyclic AMP-Dependent Protein Kinases; D000241:Adenosine