Structures of PDK1 with Bisindolylmaleimides and LY333531

Bisindolylmaleimides were also cocrystallized with PDK1 (PDB-codes 1UU7, 1UU8, 1UU9, 1UVR) (Komander et al. 2004). The structure obtained with PDK1 and BIM2 is very similar to the molecule A of our structure of PKA and BIM2, but an alternative conformation comparable to the molecule B structure of PKA with BIM2 was not observed in the case of PDK1. The hinge region contacts of the bisindolylmaleimides are conserved between the two kinases. As in PKA, BIM2 in PDK1 also shows the inwards rotation of the untethered indole. As one of the rare AGC kinase without a comparable residue to Phe327, the PDK1 structure also lacks these contacts between the inhibitor and the kinase, in this respect similar to the structure of PKA, where the corresponding peptide stretch is mobile and not resolved. As a striking difference between the two BIM2 kinase complexes, the glycine-rich loop in PDK1 shows no conformational change similar to that in PKA, and no contact between the Phe54 homologue in PDK1 is made to the pyrroli-dine-attached methyl group of BIM2. A possible reason is the exchange of Gly52 (PKA) to serine in PDK1, which reduces the flexibility of the glycine flap and might cause steric problems. As in the less-pronounced case of the Phe54 interaction with the staurosporine sugar methyl group in PKA, where other kinases that possess the corresponding residue and still do not make the contact, the real reasons for the presence or absence of this interaction may be different.

The presence of a PKA molecule which contains an upsidedown-oriented BIM2 inhibitor, in contrast to PDK1, may be facilitated by Pro124 in PKA. In the B molecule in PKA, BIM2 is wedged between Val57 from the N-lobe, and Pro124, which makes one-sixth of all VDW contacts to the inhibitor.

Atp Camp Tesmer
Fig. 15 Stereo representation of LY333531 interactions within the ATP binding pocket of PDK1. Ligand carbon atoms are in dark grey and protein carbon atoms in light grey. Hydrogen bonds are indicated by black dotted lines. A grey ribbon indicates the protein backbone. (Komander et al. 2004)

The corresponding residue is a lysine in PDK1, which would not be suitable for similar interactions.

Another PKC inhibitor of the bisindolylmaleimide class, LY333531 or ruboxistaurin, has also been cocrystallized in complex with PDK1 (PDB-code 1UU3) (Komander et al. 2004) (Fig. 15). LY333531 shows PKC isoform specificity (e.g. 80- and 60-fold selectivity for PKQ3I and PKQ3II over PKCa (Jirousek et al. 1996) and is in phase III clinical trials for diabetic retinopathy and diabetic macular oedema (Frank 2002 and citations therein). LY333531 shares much of the flexibility of BIM2, except that the cyclic connection of both N-atoms of the indoles with a 6-atom ether linker prevents a comparable inwards rotation of one indole as seen with bisindolylmaleimide 2 (Fig. 12). Komander et al. explain the higher binding affinity of inhibitors such as staurosporine, UCN01 and LY333531 in contrast to bisindolyl-maleimides by a preference of PDK1 for carbon atoms at specific positions which are satisfied by the indolocarbazoles and LY333531 but not by the bisindolylmaleimides. Mutagenesis of PDK1 and sequence comparisons, however, did not explain the selectivity of the bisindolylmaleimides and LY333531 for the PKC isoforms.


Akamine P, Madhusudan Wu J, Xuong NH, Ten Eyck LF, Taylor SS (2003) Dynamic features of cAMP-dependent protein kinase revealed by apoenzyme crystal structure. J Mol Biol 327:159-171 Alessi DR, Cohen P (1998) Mechanism of activation and function of protein kinase B.

Curr Opin Genet Dev 8:55-62 Alessi DR, Deak M, Casamayor A, Caudwell FB, Morrice N, Norman DG, Gaffney P, Reese CB, MacDougall CN, Harbison D, Ashworth A, Bownes M (1997a) 3-Phosphoinosi-tide-dependent protein kinase-1 (PDK1): structural and functional homology with the Drosophila DSTPK61 kinase. Curr Biol 7:776-789 Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB, Cohen P (1997b) Characterization of a 3-phosphoinositide-dependent protein kinase which phospho-rylates and activates protein kinase Balpha. Curr Biol 7:261-269 Amano M, Mukai H, Ono Y, Chihara K, Matsui T, Hamajima Y, Okawa K, Iwamatsu A, Kaibuchi K (1996) Identification of a putative target for Rho as the serine-threonine kinase protein kinase N. Science 271:648-650 Amano M, Fukata Y, Kaibuchi K (2000) Regulation and functions of Rho-associated kinase. Exp Cell Res 261:44-51 Aubol BE, Nolen B, Shaffer J, Ghosh G, Adams JA (2003) Novel destabilization of nucleo-tide binding by the gamma phosphate of ATP in the yeast SR protein kinase Sky1p. Biochemistry 42:12813-12820 Balendran A, Casamayor A, Deak M, Paterson A, Gaffney P, Currie R, Downes CP, Alessi DR (1999) PDK1 acquires PDK2 activity in the presence of a synthetic peptide derived from the carboxyl terminus of PRK2. Curr Biol 9:393-404 Balendran A, Biondi RM, Cheung PCF, Casamayor A, Deak M, Alessi DR (2000) A 3-phosphoinositide-dependent protein kinase-1 (PDK1) docking site is required for the phosphorylation of protein kinase C zeta (PKC zeta) and PKC-related kinase 2 by PDK1. J Biol Chem 275:20806-20813 Barbier P, Huber I, Schneider F, Stadlwieser J, Taylor S (1995) Preparation of 3-amino/hy-droxy-4-[4-benzoylphenylcarboxylamino/oxy]azepine and homolog protein kinase inhibitors. (F.Hoffmann-La Roche Ag:Switz [663393]: pp 1-47 EP663393 Barbier P, Stadlwieser J, Taylor S (1997) Novel azepanes and their ring homologs for therapy and prophylaxis of protein kinase mediated diseases. (F. Hoffmann-La Roche Ag:Switz [9702249]:pp 1-43 WO9702249 Battistutta R, De Moliner E, Sarno S, Zanotti G, Pinna LA (2001) Structural features underlying selective inhibition of protein kinase CK2 by ATP site-directed tetrabromo-2-benzotriazole. Protein Sci 10:2200-2206 Bayliss R, Sardon T, Vernos I, Conti E (2003) Structural basis of aurora-A activation by

TPX2 at the mitotic spindle. Mol Cell 12:851-862 Bertrand JA, Thieffine S, Vulpetti A, Cristiani C, Valsasina B, Knapp S, Kalisz HM, Flocco M (2003) Structural characterization of the GSK-3beta active site using selective and non-selective ATP-mimetic inhibitors. J Mol Biol 333:393-407 Biondi RM, Cheung PCF, Casamayor A, Deak M, Currie RA, Alessi DR (2000) Identification of a pocket in the PDK1 kinase domain that interacts with PIF and the C-termi-nal residues of PKA. EMBO J 19:979-988 Biondi RM, Kieloch A, Currie RA, Deak M, Alessi DR (2001) The PIF-binding pocket in PDK1 is essential for activation of S6 K and SGK, but not PKB. EMBO J 20:43804390

Biondi RM, Komander D, Thomas CC, Lizcano JM, Deak M, Alessi DR, van Aalten DMF

(2002) High resolution crystal structure of the human PDK1 catalytic domain defines the regulatory phosphopeptide docking site. EMBO J 21:4219-4228

Bossemeyer D (1994) The glycine-rich sequence of protein kinases: a multifunctional element. Trends Biochem Sci 19:201-205 Bossemeyer D, Engh RA, Kinzel V, Ponstingl H, Huber R (1993) Phosphotransferase and substrate binding mechanism of the cAMP-dependent protein-kinase catalytic subunit from porcine heart as deduced from the 2.0 angstrom structure of the complex with Mn2+ adenylyl imidodiphosphate and inhibitor peptide Pki(5-24). EMBO J 12:849-859

Breitenlechner CB, Wegge T, Berillon L, Graul K, Marzenell K, Friebe W-G, Thomas U, Schumacher R, Huber R, Engh RA, Masjost B (2004) Structure-based optimization of novel azepane derivatives as PKB inhibitors. J Med Chem 47:1375-1390 Breitenlechner CB, Gaßel M, Hidaka H, Kinzel V, Huber R, Engh RA, Bossemeyer D

(2003) Protein Kinase A in complex with Rho kinase inhibitors Y-27632, fasudil (HA-1077) and H-1152P: structural basis of selectivity. Structure 11:1595-1607

Chen HX, Marshall JL, Ness E, Martin RR, Dvorchik B, Rizvi N, Marquis J, McKinlay M, Dahut W, et al (2000) A safety and pharmacokinetic study of a mixed-backbone oligonucleotide (GEM231) targeting the type I protein kinase A by two-hour infusions in patients with refractory solid tumors. Clin Cancer Res 6:1259-1266 Cheng XD, Ma Y, Moore M, Hemmings BA, Taylor SS (1998) Phosphorylation and activation of cAMP-dependent protein kinase by phosphoinositide-dependent protein ki-nase. Proc Natl Acad Sci U S A 95:9849-9854 Davies SP, Reddy H, Caivano M, Cohen P (2000) Specificity and mechanism of action of some commonly used protein kinase inhibitors. BioChem J 351:95-105 De Azevedo WF, Jr, Mueller-Dieckmann HJ, Schulze-Gahmen U, Worland PJ, Sausville E, Kim SH (1996) Structural basis for specificity and potency of a flavonoid inhibitor of human CDK2, a cell cycle kinase. Proc Natl Acad Sci U S A 93:2735-2740

De Moliner E, Brown NR, Johnson LN (2003) Alternative binding modes of an inhibitor to two different kinases. Eur J Biochem 270:3174-3181 Dempsey EC, Newton AC, Mochly-Rosen D, Fields AP, Reyland ME, Insel PA, Messing RO (2000) Protein kinase C isozymes and the regulation of diverse cell responses. Am J Physiol Lung Cell Mol Physiol 279:L429-L438 Engh RA, Bossemeyer D (2001) The protein kinase activity modulation sites: mechanisms for cellular regulation—targets for therapeutic intervention. Adv Enzym Regul 41:121-149

Engh RA, Bossemeyer D (2002) Structural aspects of protein kinase control—role of conformational flexibility. Pharmacol Ther 93:99-111 Engh RA, Girod A, Kinzel V, Huber R, Bossemeyer D (1996) Crystal structures of catalytic subunit of cAMP-dependent protein kinase in complex with isoquinolinesulfonyl protein kinase inhibitors H7, H8, and H89. Structural implications for selectivity. J Biol Chem 271:26157-26164 Fabbro D, Ruetz S, Bodis S, Pruschy M, Csermak K, Man A, Campochiaro P, Wood J, O'Reilly T, Meyer T (2000) PKC412—a protein kinase inhibitor with a broad therapeutic potential. Anticancer Drug Des 15:17-28 Fabbro D, Ruetz S, Buchdunger E, Cowan-Jacob SW, Fendrich G, Liebetanz J, Mestan J, O'Reilly T, Traxler P, Chaudhuri B, Fretz H, Zimmermann J, Meyer T, Caravatti G, Furet P, Manley PW (2002) Protein kinases as targets for anticancer agents: from inhibitors to useful drugs. Pharmacol Ther 93:79-98 Flynn P, Mellor H, Casamassima A, Parker PJ (2000) Rho GTPase control of protein ki-nase C-related protein kinase activation by 3-phosphoinositide-dependent protein kinase. J Biol Chem 275:11064-11070 Fox T, Coll JT, Xie XL, Ford PJ, Germann UA, Porter MD, Pazhanisamy S, Fleming MA, Galullo V, Su MSS, Wilson KP (1998) A single amino acid substitution makes ERK2 susceptible to pyridinyl imidazole inhibitors of p38 MAP kinase. Protein Sci 7:22492255

Frank RN (2002) Potential new medical therapies for diabetic retinopathy: protein kinase

C inhibitors. Am J Ophthalmol 133:693-698 Frodin M, Jensen CJ, Merienne K, Gammeltoft S (2000) A phosphoserine-regulated docking site in the protein kinase RSK2 that recruits and activates PDK1. EMBO J 19:2924-2934

Frodin M, Antal TL, Dummler BA, Jensen CJ, Deak M, Gammeltoft S, Biondi RM (2002) A phosphoserine/threonine-binding pocket in AGC kinases and PDK1 mediates activation by hydrophobic motif phosphorylation. EMBO J 21:5396-5407 Fukata Y, Amano M, Kaibuchi K (2001) Rho-Rho kinase pathway in smooth muscle contraction and cytoskeletal reorganization of non-muscle cells. Trends Pharmacol Sci 22:32-39

Ganeshaguru K, Wickremasinghe RG, Jones DT, Gordon M, Hart SM, Virchis AE, Prentice HG, Hoffbrand AV, Man A, Champain K, Csermak K, Mehta AB (2002) Actions of the selective protein kinase C inhibitor PKC412 on B-chronic lymphocytic leukemia cells in vitro. Haematologica 87:167-176 Gao T, Toker A, Newton AC (2001) The carboxyl terminus of protein kinase C provides a switch to regulate its interaction with the phosphoinositide-dependent kinase, PDK-1. J Biol Chem 276:19588-19596 Gaßel M, Breitenlechner CB, König N, Huber R, Engh RA, Bossemeyer D (2004) The protein kinase C inhibitor bisindolyl-maleimide II binds with reversed orientations to different conformations of PKA. J Biol Chem (in press)

Gaßel M, Breitenlechner CB, Ruger P, Jucknischke U, Schneider T, Huber R, Bossemeyer D, Engh RA (2003) Mutants of protein kinase A that mimic the ATP-binding site of protein kinase B (AKT). J Mol Biol 329:1021-1034 Gescher A (2000) Staurosporine analogues—pharmacological toys or useful antitumour agents? Crit Rev Oncol Hematol 34:127-135 Gibbs CS, Knighton DR, Sowadski JM, Taylor SS, Zoller MJ (1992) Systematic mutational analysis of cAMP-dependent protein kinase identifies unregulated catalytic subunits and defines regions important for the recognition of the regulatory subunit. J Biol Chem 267:4806-4814

Gustafsson AB, Brunton LL (1999) Differential and selective inhibition of protein kinase A and protein kinase C in intact cells by balanol congeners. Mol Pharmacol 56:37782

Hall SE, Ballas LM, Kulanthaivel P, et al (1994) Preparation of balanoids as protein kinase C inhibitors. (Nichols:Gina M USA Sphinx Pharmaceuticals Corporation [9420062]):pp 1-559 W09420062 Hanks SK, Quinn AM (1991) Protein kinase catalytic domain sequence database: identification of conserved features of primary structure and classification of family members. Methods Enzymol 200:38-62 Hofmann J (2001) Modulation of protein kinase C in antitumor treatment. Rev Physiol

Biochem Pharmacol 142:1-96 Hu H, Jagdmann EG Jr, Mendoza JS (1995) Preparation of substituted fused and bridged bicyclic compound protein kinase C inhibitors. (Lilly:Eli Co USA [9530640]:pp 1-84 1995 W09530640

Hubbard SR (1997) Crystal structure of the activated insulin receptor tyrosine kinase in complex with peptide substrate and ATP analog. EMBO J 16:5572-5581 Hunenberger PH, Helms V, Narayana N, Taylor SS, McCammon JA (1999) Determinants of ligand binding to cAMP-dependent protein kinase. Biochemistry 38:2358-2366 Huse M, Kuriyan J (2002) The conformational plasticity of protein kinases. Cell 109:275282

Ikenoya M, Hidaka H, Hosoya T, Suzuki M, Yamamoto N, Sasaki Y (2002) Inhibition of Rho kinase-induced myristoylated alanine-rich C kinase substrate (MARCKS) phosphorylation in human neuronal cells by H-1152, a novel and specific Rho kinase inhibitor. J Neurochem 81:9-16 Inoue M, Kishimoto A, Takai Y, Nishizuka Y (1977) Studies on a cyclic nucleotide-inde-pendent protein kinase and its proenzyme in mammalian tissues. II Proenzyme and its activation by calcium-dependent protease from rat brain. J Biol Chem 252:76107616

Ishizaki T, Uehata M, Tamechika I, Keel J, Nonomura K, Maekawa M, Narumiya S (2000) Pharmacological properties of Y-27632, a specific inhibitor of Rho-associated kinas-es. Mol Pharmacol 57:976-983 Itoh K, Yoshioka K, Akedo H, Uehata M, Ishizaki T, Narumiya S (1999) An essential part for Rho-associated kinase in the transcellular invasion of tumor cells. Nat Med 5:221-225

Jagdmann GE, Defauw JM, Lampe JW, Darges JW, Kalter K (1996) Potent and selective PKC inhibitory 5-membered ring analogs of balanol with replacement of the carbox-amide moiety. Bioorg Med Chem Lett 6:1759-1764 Jensen CJ, Buch MB, Krag TO, Hemmings BA, Gammeltoft S, Frodin M (1999) 90-kDa ri-bosomal S6 kinase is phosphorylated and activated by 3-phosphoinositide-depen-dent protein kinase-1. J Biol Chem 274:27168-27176

Jirousek MR, Gillig JR, Gonzalez CM, Heath WF, McDonald JH, III Neel DA, Rito CJ, Singh U, Stramm LE, Melikian-Badalian A, Baevsky M, Ballas LM, Hall SE, Win-neroski LL, Faul MM (1996) (S)-13-[(dimethylamino)methyl]-10,11,14,15-tetrahy-dro-4,9:16, 21-dimetheno-1H, 13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclo-hexadecene-1,3(2H)-d ione (LY333531) and related analogues: isozyme selective inhibitors of protein kinase C beta. J Med Chem 39:2664-2671 Johnson DA, Li F, Gangal M, Juliano C, Gorfain E, Taylor SS (2002a) Domain closure, segmental flexibility, and the catalytic cycle of A-kinase. Biophys J 82:1624 Johnson LN, De Moliner E, Brown NR, Song H, Barford D, Endicott JA, Noble MEM (2002b) Structural studies with inhibitors of the cell cycle regulatory kinase cyclin-dependent protein kinase 2. Pharmacol Ther 93:113-124 Karlsson R, Zheng JH, Xuong NH, Taylor SS, Sowadski JM (1993) Structure of the mammalian catalytic subunit of cAMP-dependent protein-kinase and an inhibitor peptide displays an open conformation. Acta Crystallogr D Biol Crystallogr 49:381-388 Kim DW, Hwang JH, Suh JM, Kim H, Song JH, Hwang ES, Hwang IY, Park KC, Chung HK, Kim JM, Park J, Hemmings BA, Shong M (2003) RET/PTC (rearranged in transformation/papillary thyroid carcinomas) tyrosine kinase phosphorylates and activates phosphoinositide-dependent kinase 1 (PDK1): an alternative phosphatidylino-sitol 3-kinase-independent pathway to activate PDK1. Mol Endocrinol 17:1382-1394 Kinzel V, Kubler D (1976) Single step purification of the catalytic subunit(s) of cyclic 3', 5'-adenosine monophosphate-dependent protein kinase(s) from rat muscle. Biochem Biophys Res Commun 71:257-264 Kishimoto A, Takai Y, Nishizuka Y (1977) Activation of glycogen phosphorylase kinase by a calcium-activated, cyclic nucleotide-independent protein kinase system. J Biol Chem 252:7449-7452

Knighton DR, Zheng JH, Ten Eyck LF, Ashford VA, Xuong NH, Taylor SS, Sowadski JM (1991) Crystal structure of the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase [see comments]. Science 253:407-414 Kobayashi T, Cohen P (1999) Activation of serum- and glucocorticoid-regulated protein kinase by agonists that activate phosphatidylinositide 3-kinase is mediated by 3-phosphoinositide-dependent protein kinase-1 (PDK1) and PDK2. Biochem J 339:319-328

Koide K, Bunnage ME, Gomez Paloma L, Kanter JR, Taylor SS, Brunton LL, Nicolaou KC (1995) Molecular design and biological activity of potent and selective protein kinase inhibitors related to balanol. Chem Biol 2:601-8 Komander D, Kular GS, Bain J, Elliott M, Alessi DR, van Aalten DMF (2003) Structural basis for UCN-01 (7-hydroxystaurosporine) specificity and PDK1 (3-phosphoinosi-tide-dependent protein kinase-1) inhibition. BioChem J 375:255-262 Komander D, Kular GS, Schüttelkopf AW, Deak M, Prakash KRC, Bain J, Elliott M, Garrido-'Franko M, Kozikowski AP, Alessi DR, van Aalten DMF (2004) Interactions of LY333531 and other bisindolyl maleimide inhibitors with PDK1. Structure 12:215-226

Kubler D, Gagelmann M, Pyerin W, Kinzel V (1979) Isolation of the catalytic subunits of cyclic AMP-dependent protein kinases from different mammalian tissues on the basis of charge differences of their subunits. Hoppe Seylers Z Physiol Chem 360:14211431

Kulanthaivel P, Hallock Y, Boros C, Hamilton SM, Janzen WP, Ballas LM, Loomis CR, Jiang JB, Katz JB, Steiner JR, Clardy J (1993) Balanol: a novel and potent inhibitor of protein kinase C from the fungus Verticillium balanoides. J Am Chem Soc 115:64526453

Lamers MB, Antson AA, Hubbard RE, Scott RK, Williams DH (1999) Structure of the protein tyrosine kinase domain of C-terminal Src kinase (CSK) in complex with staurosporine. J Mol Biol 285:713-725 Lampe JW, Biggers CK, Defauw JM, Foglesong RJ, Hall SE, Heerding JM, Hollinshead SP, Hu H, Hughes PF, Jagdmann GE, Jr, Johnson MG, Lai YS, Lowden CT, Lynch MP, Mendoza JS, Murphy MM, Wilson JW, Ballas LM, Carter K, Darges JW, Davis JE, Hubbard FR, Stamper ML (2002) Synthesis and protein kinase inhibitory activity of balanol analogues with modified benzophenone subunits. J Med Chem 45:2624-43 Lawrie AM, Noble ME, Tunnah P, Brown NR, Johnson LN, Endicott JA (1997) Protein ki-nase inhibition by staurosporine revealed in details of the molecular interaction with CDK2 [letter]. Nat Struct Biol 4:796-801 Le Good JA, Ziegler WH, Parekh DB, Alessi DR, Cohen P, Parker PJ (1998) Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1. Science 281:2042-2045 Leung T, Manser E, Tan L, Lim L (1995) A novel serine/threonine kinase binding the Ras-related RhoA GTPase which translocates the kinase to peripheral membranes. J Biol Chem 270:29051-29054 Lodowski DT, Pitcher JA, Capel WD, Lefkowitz RJ, Tesmer JJG (2003) Keeping G proteins at bay: a complex between G protein-coupled receptor kinase 2 and Gbetagamma. Science 300:1256-1262 Madhusudan Akamine P, Xuong NH, Taylor SS (2002) Crystal structure of a transition state mimic of the catalytic subunit of cAMP-dependent protein kinase. Nat Struct Biol 9:273-277

Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S (2002) The protein kinase complement of the human genome. Science 298:1912-1934 Marambaud P, Ancolio K, Alves da Costa C, Checler F (1999) Effect of protein kinase A inhibitors on the production of Abeta40 and Abeta42 by human cells expressing normal and Alzheimer's disease-linked mutated betaAPP and presenilin 1. Br J Pharmacol 126:1186-1190

Matsui T, Amano M, Yamamoto T, Chihara K, Nakafuku M, Ito M, Nakano T, Okawa K, Iwamatsu A, Kaibuchi K (1996) Rho-associated kinase, a novel serine threonine kinase, as a putative target for the small GTP binding protein Rho. EMBO J 15:22082216

Meggio F, Donella DA, Ruzzene M, et al (1995) Different susceptibility of protein kinases to staurosporine inhibition. Kinetic studies and molecular bases for the resistance of protein kinase CK2. Eur J Biochem 234:317-322 Montminy M (1997) Transcriptional regulation by cyclic AMP. Annu Rev Biochem 66:807-822

Nakashima S (2002) Protein kinase C alpha (PKC alpha): regulation and biological function. J Biochem (Tokyo) 132:669-675 Narayana N, Diller TC, Koide K, Bunnage ME, Nicolaou KC, Brunton LL, Xuong NH, Ten Eyck LF, Taylor SS (1999) Crystal structure of the potent natural product inhibitor balanol in complex with the catalytic subunit of cAMP-dependent protein kinase. Biochemistry 38:2367-2376 Narumiya S, Ishizaki T, Uehata M (2000) Use and properties of ROCK-specific inhibitor

Y-27632. Methods Enzymol 325:273-284 Nelson NC, Taylor SS (1981) Differential labeling and identification of the cysteine- containing tryptic peptides of catalytic subunit from porcine heart cAMP-dependent protein kinase. J Biol Chem 256:3743-3750

Newton AC (2001) Protein kinase C: structural and spatial regulation by phosphorylation, cofactors, and macromolecular interactions. Chem Rev 101:2353-2364 Newton AC (2003) Regulation of the ABC kinases by phosphorylation: protein kinase C

as a paradigm. BioChem J 370:361-371 Nishizuka Y (1984) The role of protein kinase C in cell surface signal transduction and tumour promotion. Nature 308:693-698 Nishizuka Y (1995) Protein kinase C and lipid signaling for sustained cellular responses. FASEB J 9:484-496

Nolen B, Ngo J, Chakrabarti S, Vu D, Adams JA, Ghosh G (2003) Nucleotide-induced con-formational changes in the Saccharomyces cerevisiae SR protein kinase, Sky1p, revealed by X-ray crystallography. Biochemistry 42:9575-9585 Ohshima S, Yanagisawa M, Katoh A, Fujii T, Sano T, Matsukuma S, Furumai T, Fujiu M, Watanabe K, Yokose K, et al (1994) Fusarium merismoides Corda NR 6356, the source of the protein kinase C inhibitor, azepinostatin. Taxonomy, yield improvement, fermentation and biological activity. J Antibiot (Tokyo) 47:639-47 Olah GA, Mitchell RD, Sosnick TR, Walsh DA, Trewhella J (1993) Solution structure of the cAMP-dependent protein kinase catalytic subunit and its contraction upon binding the protein kinase inhibitor peptide. Biochemistry 32:3649-3657 Ono-Saito N, Niki I, Hidaka H (1999) H-series protein kinase inhibitors and potential clinical applications. Pharmacol Ther 82:123-131 Orellana SA, Amieux PS, Zhao X, McKnight GS (1993) Mutations in the catalytic subunit of the cAMP-dependent protein kinase interfere with holoenzyme formation without disrupting inhibition by protein kinase inhibitor. J Biol Chem 268:6843-6846 Pargellis C, Tong L, Churchill L, Cirillo PF, et al (2002) Inhibition of p38 MAP kinase by utilizing a novel allosteric binding site. Nat Struct Biol 9:268-272 Park J, Hill MM, Hess D, Brazil DP, Hofsteenge J, Hemmings BA (2001) Identification of tyrosine phosphorylation sites on 3-phosphoinositide-dependent protein kinase-1 and their role in regulating kinase activity. J Biol Chem 276:37459-37471 Pettit GR, Day JF, Hartwell JL, Wood HB (1970) Antineoplastic components of marine animals. Nature 227:962-963 Prade L, Engh RA, Girod A, Kinzel V, Huber R, Bossemeyer D (1997) Staurosporine-in-duced conformational changes of cAMP-dependent protein kinase catalytic subunit explain inhibitory potential. Structure 5:1627-1637 Pullen N, Dennis PB, Andjelkovic M, Dufner A, Kozma SC, Hemmings BA, Thomas G

(1998) Phosphorylation and activation of p70s6 k by PDK1. Science 279:707-710 Richards SA, Fu J, Romanelli A, Shimamura A, Blenis J (1999) Ribosomal S6 kinase 1 (RSK1) activation requires signals dependent on and independent of the MAP kinase ERK. CurrBiol 9:810-820 Russo AA, Jeffrey PD, Pavletich NP (1996) Structural basis of cyclin-dependent kinase activation by phosphorylation. Nat Struct Biol 3:696-700 Sasaki Y, Suzuki M, Hidaka H (2002) The novel and specific Rho kinase inhibitor (S)-(+)-2-methyl-1- [(4-methyl-5-isoquinoline)sulfonyl]-homopiperazine as a probing molecule for Rho kinase-involved pathway. Pharmacol Ther 93:225-232 Schneider T (2002) Kinetische und strukturelle Untersuchungen zur Funktion ausgewählter konservierter Aminosäurereste der katalytischen Untereinheit Ca der Pro-teinkinase A. Universität Bielefeld Schulze Gahmen U, Brandsen J, Jones HD, Morgan DO, Meijer L, Vesely J, Kim SH (1995) Multiple modes of ligand recognition: crystal structures of cyclin-dependent protein kinase 2 in complex with ATP and two inhibitors, olomoucine and isopentenylade-nine. Proteins 22:378-391

Setyawan J, Koide K, Diller TC, Bunnage ME, Taylor SS, Nicolaou KC, Brunton LL (1999) Inhibition of protein kinases by balanol: Specificity within the serine/threonine protein kinase subfamily. Mol Pharmacol 56:370-376 Shimokawa H, Iinuma H, Kishida H, Nakashima M, Kato K (2001) Antianginal effect of fasudil, a Rho kinase inhibitor, in patients with stable effort angina: a multicenter study. Circulation 104:2843 Sicheri F, Moarefi I, Kuriyan J (1997) Crystal structure of the Src family tyrosine kinase

Hck [see comments]. Nature 385:602-609 Sinnett-Smith J, Lunn JA, Leopoldt D, Rozengurt E (2001) Y-27632, an inhibitor of Rho-associated kinases, prevents tyrosine phosphorylation of focal adhesion kinase and paxillin induced by bombesin: dissociation from tyrosine phosphorylation of p130(CAS). Exp Cell Res 266:292-302 Sprang SR, Acharya KR, Goldsmith EJ, Stuart DI, Varvill K, Fletterick RJ, Madsen NB, Johnson LN (1988) Structural changes in glycogen phosphorylase induced by phos-phorylation. Nature 336:215-221 Stokoe D, Stephens LR, Copeland T, Gaffney PR, Reese CB, Painter GF, Holmes AB, McCormick F, Hawkins PT (1997) Dual role of phosphatidylinositol-3,4,5-trisphos-phate in the activation of protein kinase B. Science 277:567-570 Swannie HC, Kaye SB (2002) Protein kinase C inhibitors. Curr Oncol Rep 4:37-46 Takemoto M, Sun JX, Hiroki J, Shimokawa H, Liao JK (2002) Rho kinase mediates hypox-ia-induced downregulation of endothelial nitric oxide synthase. Circulation 106:5762

Tamm I, Dorken B, Hartmann G (2001) Antisense therapy in oncology: new hope for an old idea? Lancet 358:489-497 Tanaka H, Ohshima N, Takagi M, Komeima K, Hidaka H (1998) Novel vascular relaxant, Hmn-1152—its molecular mechanism of action. Naunyn Schmiedebergs Arch Phar-makol 358:P3740

Taniyama Y, Weber DS, Rocic P, Hilenski L, Akers ML, Park J, Hemmings BA, Alexander RW, Griendling KK (2003) Pyk2-dependent tyrosine phosphorylation of PDK1 mediates cell spreading. FASEB J 17:A1351 Toledo LM, Lydon NB (1997) Structures of staurosporine bound to CDK2 and cAPK— new tools for structure-based design of protein kinase inhibitors. Structure 5:15511556

Trauger JW, Lin FF, Turner MS, Stephens J, LoGrasso PV (2002) Kinetic mechanism for human Rho-kinase II (ROCK-II). Biochemistry 41:8948-8953 Traxler P (2003) Tyrosine kinases as targets in cancer therapy—successes and failures.

Expert Opin Ther Targets 7:215-234 Uehata M, Ishizaki T, Satoh H, Ono T, Kawahara T, Morishita T, Tamakawa H, Yamagami K, Inui J, Maekawa M, Narumiya S (1997) Calcium sensitization of smooth muscle mediated by a Rho- associated protein kinase in hypertension. Nature 389:990-994 Underwood KW, Parris KD, Federico E, et al (2003) Catalytically active MAP KAP kinase 2 structures in complex with staurosporine and ADP reveal differences with the au-toinhibited enzyme. Structure 11:627-636 Vanhaesebroeck B, Alessi DR (2000) The P13K-PDK1 connection: more than just a road to PKB. BioChem J 346:561-576 Walsh DA, Perkins JP, Krebs EG (1968) An adenosine 3',5'-monophosphate-dependant protein kinase from rabbit skeletal muscle. J Biol Chem 243:3763-3765 Way KJ, Chou E, King GL (2000) Identification of PKC-isoform-specific biological actions using pharmacological approaches. Trends Pharmacol Sci 21:181-187

Wick MJ, Wick KR, Chen H, He H, Dong LQ, Quon MJ, Liu F (2002) Substitution of the autophosphorylation site Thr516 with a negatively charged residue confers constitutive activity to mouse 3-phosphoinositide-dependent protein kinase-1 in cells. J Biol Chem 277:16632-16638 Wong CF, Hunenberger PH, Akamine P, Narayana N, Diller T, McCammon JA, Taylor S, Xuong NH (2001) Computational analysis of PKA-balanol interactions. J Med Chem 44:1530-1539

Xu R-M, Carmel G, Kuret J, Cheng X (1996) Structural basis for selectivity of the iso-quinoline sulfonamide family of protein kinase inhibitors. Proc Natl Acad Sci USA 93:6308-6313

Yang J, Cron P, Good VM, Thompson V, Hemmings BA, Barford D (2002) Crystal structure of an activated Akt/protein kinase B ternary complex with GSK3-peptide and AMP-PNP. Nat Struct Biol 9:940-944 Zhao B, Bower MJ, McDevitt PJ, Zhao HZ, Davis ST, Johanson KO, Green SM, Concha NO, Zhou BBS (2002) Structural basis for Chk1 inhibition by UCN-01. J Biol Chem 277:46609-46615

Zheng J, Knighton DR, Ten Eyck LF, Karlsson R, Xuong N, Taylor SS, Sowadski JM (1993) Crystal structure of the catalytic subunit of cAMP-dependent protein kinase com-plexed with MgATP and peptide inhibitor. Biochemistry 32:2154-2161 Zhu X, Kim JL, Newcomb JR, Rose PE, Stover DR, Toledo LM, Zhao H, Morgenstern KA (1999) Structural analysis of the lymphocyte-specific kinase Lck in complex with non-selective and Src family selective kinase inhibitors. Structure Fold Des 7:651661

HEP (2005) 167:125-155 © Springer-Verlag 2005

Was this article helpful?

0 0

Post a comment