BIM-1 explained

BIM-1 (GF 109203X) and the related compounds BIM-2, BIM-3, and BIM-8 are bisindolylmaleimide-based protein kinase C (PKC) inhibitors. These inhibitors also inhibit PDK1 explaining the higher inhibitory potential of LY33331 compared to the other BIM compounds a bisindolylmaleimide inhibitor toward PDK1.[1] [2]

Function

BIM-1 is present in the structure of PKCiota[3] (residue 574-turn[4] motif). It needs to be phosphorylated towards a PKCbeta-specific inhibitor site-directed mutagenesis of the compound for its full activation[5] and co-crystallized as an asymmetric pair which is mediated by 3-phosphoinositide-dependent protein kinase-1 (PDK1)[6] are downstream characteristics of PKCs and PKB/AKT.[7]

Scope

The bound BIM-1 inhibitor blocks bilobal[8] interactions, the ATP-binding site, features an ATP-competitive inhibitor, 2-methyl-1H-indol-3-yl-BIM-1, the crystal structure[8] and catalytic subunit with a 20-amino acid substrate analog inhibitor structure is bilobal MgATP a transport protein that provide a more precise description of which is influenced by lobe-lobe interactions binding in cells expressing both forms a pair of kinase-inhibitor complexes[7] with ferritin in a soluble and non-toxic form (Poisson-Boltzmann[9]) and a portion of the inhibitor peptide[10] a lysine residue, has been shown to be involved in ATP binding.

Interactions

The PKCiota-BIM-1 complex[4] interacts with the zinc finger of lambda/iota PKC characterization of lambda-interacting protein (LIP) (lambda-interacting protein; a selective activator of lambda/iota PKC). Phosphorylation of a PKC induces a conformation leading to import of a PKC into the nucleus.[11] The entire 587-amino acid coding region of a new PKC isoform, PKC iota.[11] Where Thr-412[12] (activation loop of the kinase domain) at PKCiota/lambda phosphorylates glyceraldehyde-3-phosphate dehydrogenase (GAPDH)[13] that sort cargo to the anterograde pathway[14] the phosphorylation pathway(s) involved in this phenomenon[2] mimic glutamate and can adopt two limiting diastereomeric (syn and anti) conformation[15] biosynthetically related indolocarbazole analogs[16] and in Proto-oncogene serine/threonine-protein kinase Pim-1-Peptide as a phosphorylation target including itself. The bound BIM-1 inhibitor blocks the ATP-binding site and puts the kinase domain into an intermediate open[7] conformation.[4] The value of such calculations lies in understanding a variant was designed which showed improved binding characteristics[17] of configurationally stable atropisomeric bisindolylmaleimides where the two kinase domains, and two different inhibitor conformers bind in different orientations, the hinge region of staurosporine[18] -Pim-1 resembles[19] co-crystallized[8] as an asymmetric pair of biosynthetically 'related' indolocarbazole analogs. It is a modulator of the 5-HT2A receptor.[20]

Notes and References

  1. Komander D, Kular GS, Schüttelkopf AW, Deak M, Prakash KR, Bain J, Elliott M, Garrido-Franco M, Kozikowski AP, Alessi DR, van Aalten DM . Interactions of LY333531 and other bisindolyl maleimide inhibitors with PDK1 . Structure . 12 . 2 . 215–26 . February 2004 . 14962382 . 10.1016/j.str.2004.01.005 . free .
  2. Cartee L, Smith R, Dai Y, Rahmani M, Rosato R, Almenara J, Dent P, Grant S . Synergistic induction of apoptosis in human myeloid leukemia cells by phorbol 12-myristate 13-acetate and flavopiridol proceeds via activation of both the intrinsic and tumor necrosis factor-mediated extrinsic cell death pathways . Mol. Pharmacol. . 61 . 6 . 1313–21 . June 2002 . 12021392. 10.1124/mol.61.6.1313 .
  3. Baldwin RM, Parolin DA, Lorimer IA . Regulation of glioblastoma cell invasion by PKC iota and RhoB. Oncogene . 27 . 25 . 3587–95 . June 2008 . 18212741 . 10.1038/sj.onc.1211027 . free .
  4. Messerschmidt A, Macieira S, Velarde M, Bädeker M, Benda C, Jestel A, Brandstetter H, Neuefeind T, Blaesse M . Crystal structure of the catalytic domain of human atypical protein kinase C-iota reveals interaction mode of phosphorylation site in turn motif . J Mol Biol . 352 . 4 . 918–31 . September 2005 . 16125198 . 10.1016/j.jmb.2005.07.060 .
  5. Diaz-Meco MT, Municio MM, Sanchez P, Lozano J, Moscat J . Lambda-interacting protein, a novel protein that specifically interacts with the zinc finger domain of the atypical protein kinase C isotype lambda/iota and stimulates its kinase activity in vitro and in vivo . Mol Cell Biol . 16 . 1 . 105–14 . January 1996 . 8524286 . 10.1128/mcb.16.1.105. 230983 .
  6. Peifer C, Alessi DR . Small-molecule inhibitors of PDK1 . ChemMedChem . 3 . 12 . 1810–38 . December 2008 . 18972468 . 10.1002/cmdc.200800195 . 29838120 .
  7. Gassel M, Breitenlechner CB, König N, Huber R, Engh RA, Bossemeyer D . The protein kinase C inhibitor bisindolyl maleimide 2 binds with reversed orientations to different conformations of protein kinase A . J Biol Chem . 279 . 22 . 23679–90 . May 2004 . 14996846 . 10.1074/jbc.M314082200 . free .
  8. Grodsky Grodsky N, Li Y, Bouzida D, Love R, Jensen J, Nodes B, Nonomiya J, Grant S . Structure of the catalytic domain of human protein kinase C beta II complexed with a bisindolylmaleimide inhibitor . Biochemistry . 45 . 47 . 13970–81 . November 2006 . 17115692. 10.1021/bi061128h .
  9. Page CS, Bates PA . Can MM-PBSA calculations predict the specificities of protein kinase inhibitors? . J. Comput. Chem. . 27 . 16 . 1990–2007 . December 2006 . 17036304 . 10.1002/jcc.20534 . 23077429 .
  10. Knighton DR, Zheng JH, Ten Eyck LF, Ashford VA, Xuong NH, Taylor SS, Sowadski JM . Crystal structure of the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase . Science . 253 . 5018 . 407–14 . July 1991 . 1862342 . 10.1126/science.1862342 . 1991Sci...253..407K .
  11. White WO, Seibenhener ML, Wooten MW . Phosphorylation of tyrosine 256 facilitates nuclear import of atypical protein kinase C . J Cell Biochem . 85. 1 . 42–53 . January 2002 . 11891849 . 10.1002/jcb.10101 . 221311830 .
  12. Cantin GT, Yi W, Lu B, Park SK, Xu T, Lee JD, Yates JR . Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient phosphoproteomic analysis . J Proteome Res . 7 . 3 . 1346–51 . March 2008 . 18220336 . 10.1021/pr0705441 .
  13. Tisdale EJ. . Rab2 interacts directly with atypical protein kinase C (aPKC) iota/lambda and inhibits aPKCiota/lambda-dependent glyceraldehyde-3-phosphate dehydrogenase phosphorylation . J Biol Chem . 278 . 52 . 52424–30 . December 2003 . 14570876 . 10.1074/jbc.M309343200 . free .
  14. Tisdale EJ, Artalejo CR . Src-dependent aprotein kinase C iota/lambda (aPKCiota/lambda) tyrosine phosphorylation is required for aPKCiota/lambda association with Rab2 and glyceraldehyde-3-phosphate dehydrogenase on pre-golgi intermediates . J Biol Chem . 281 . 13 . 8436–42 . March 2006 . 16452474 . 10.1074/jbc.M513031200 . 3742308. free .
  15. Barrett S, Bartlett S, Bolt A, Ironmonger A, Joce C, Nelson A, Woodhall T . Configurational stability of bisindolylmaleimide cyclophanes: from conformers to the first configurationally stable, atropisomeric bisindolylmaleimides . Chemistry: A European Journal . 11 . 21 . 6277–85 . October 2005 . 16075446 . 10.1002/chem.200500520 .
  16. Sánchez C, Méndez C, Salas JA . Indolocarbazole natural products: occurrence, biosynthesis, and biological activity . Nat Prod Rep . 23 . 6 . 1007–45 . December 2006 . 17119643 . 10.1039/B601930G .
  17. Bandeiras TM, Hillig RC, Matias PM, Eberspaecher U, Fanghänel J, Thomaz M, Miranda S, Crusius K, Pütter V, Amstutz P, Gulotti-Georgieva M, Binz HK, Holz C, Schmitz AA, Lang C, Donner P, Egner U, Carrondo MA, Müller-Tiemann B . Structure of wild-type Plk-1 kinase domain in complex with a selective DARPin . Acta Crystallogr D . 64 . 4 . 339–53 . April 2008 . 18391401 . 10.1107/S0907444907068217 .
  18. Lee SK, Stern PH . Divergent effects of protein kinase C (PKC) inhibitors staurosporine and bisindolylmaleimide I (GF109203X) on bone resorption . Biochem. Pharmacol. . 60 . 7 . 923–6 . October 2000 . 10974200. 10.1016/S0006-2952(00)00418-4 .
  19. M.D.Jacobs . J.Black . O.Futer . L.Swenson . B.Hare . M.Fleming . K.Saxena . Pim-1 ligand-bound structures reveal the mechanism of serine/threonine kinase inhibition by LY294002 . J Biol Chem . 280 . 14 . 13728–13734 . May 2005 . 15657054 . 10.1074/jbc.M413155200 . free .
  20. Minami K, Minami M, Harris RA. Inhibition of 5-hydroxytryptamine type 2A receptor-induced currents by n-alcohols and anesthetics. J Pharmacol Exp Ther. 1997 Jun;281(3):1136-43.

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