title: Homology modeling and ligand docking of Mitogen-activated protein kinase-activated protein kinase 5 (MK5).
abstract: BACKGROUND
  Mitogen-activated protein kinase-activated protein kinase 5 (MK5) is involved in one of the major signaling pathways in cells, the mitogen-activated protein kinase pathway. MK5 was discovered in 1998 by the groups of Houng Ni and Ligou New, and was found to be highly conserved throughout the vertebrates. Studies, both in vivo and in vitro, have shown that it is implicated in tumor suppression as well as tumor promotion, embryogenesis, anxiety, locomotion, cell motility and cell cycle regulation.
  
  
  METHODS
  In order to obtain a molecular model of MK5 that can be used as a working tool for development of chemical probes, three MK5 models were constructed and refined based on three different known crystal structures of the closely related MKs; MK2 [PDB: 2OZA and PDB: 3M2W] and MK3 [PDB: 3FHR]. The main purpose of the present MK5 molecular modeling study was to identify the best suited template for making a MK5 model. The ability of the generated models to effectively discriminate between known inhibitors and decoys was analyzed using receiver operating characteristic (ROC) curves.
  
  
  RESULTS
  According to the ROC curve analyzes, the refined model based on 3FHR was most effective in discrimination between known inhibitors and decoys.
  
  
  CONCLUSIONS
  The 3FHR-based MK5 model may serve as a working tool for development of chemical probes using computer aided drug design. The biological function of MK5 still remains elusive, but its role as a possible drug target may be elucidated in the near future.
authors.affiliation: Medical Pharmacology and Toxicology, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, Tromsø No-9037, Norway. Aina.W.Ravna@uit.no.
authors.forename: Inger
authors.initials: I
authors.lastname: Lindin
authors.forename: Yimingjiang
authors.initials: Y
authors.lastname: Wuxiuer
authors.forename: Irina
authors.initials: I
authors.lastname: Kufareva
authors.forename: Ruben
authors.initials: R
authors.lastname: Abagyan
authors.forename: Ugo
authors.initials: U
authors.lastname: Moens
authors.forename: Ingebrigt
authors.initials: I
authors.lastname: Sylte
authors.forename: Aina Westrheim
authors.initials: AW
authors.lastname: Ravna
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D020128:Inhibitory Concentration 50; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D008024:Ligands; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D012372:ROC Curve; D055672:Static Electricity; D040681:Structural Homology, Protein
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D047428:Protein Kinase Inhibitors; C111049:MAP-kinase-activated kinase 5; D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases
references.citation: EMBO J. 2004 Dec 8;23(24):4770-9
references.pmid: 15538386
references.citation: Nat Chem Biol. 2006 Jul;2(7):358-64
references.pmid: 16783341
references.citation: J Mol Graph. 1990 Mar;8(1):52-6, 29
references.pmid: 2268628
references.citation: Nat Rev Mol Cell Biol. 2006 Feb;7(2):120-30
references.pmid: 16421520
references.citation: Cell. 2007 Jan 26;128(2):295-308
references.pmid: 17254968
references.citation: Bioorg Med Chem Lett. 2010 Aug 1;20(15):4719-23
references.pmid: 20591669
references.citation: Biochem Biophys Res Commun. 1998 Feb 13;243(2):492-6
references.pmid: 9480836
references.citation: Nucleic Acids Res. 2003 Jul 1;31(13):3503-6
references.pmid: 12824354
references.citation: Cell Cycle. 2008 Feb 1;7(3):325-34
references.pmid: 18235225
references.citation: Nature. 1996 May 23;381(6580):272
references.pmid: 8692262
references.citation: J Biol Chem. 2008 Apr 18;283(16):11014-23
references.pmid: 18268017
references.citation: Bioinformatics. 2000 Jun;16(6):566-7
references.pmid: 10980157
references.citation: J Cell Physiol. 2008 Dec;217(3):778-88
references.pmid: 18720373
references.citation: Mol Cell Biol. 2012 Feb;32(3):606-18
references.pmid: 22124154
references.citation: Behav Brain Funct. 2007 Nov 12;3:58
references.pmid: 17997833
references.citation: Cell Signal. 2009 May;21(5):712-8
references.pmid: 19166925
references.citation: J Mol Biol. 2000 Sep 8;302(1):205-17
references.pmid: 10964570
references.citation: Nat Cell Biol. 2011 Mar;13(3):263-72
references.pmid: 21336308
references.citation: J Mol Biol. 2007 Jun 8;369(3):735-45
references.pmid: 17449059
references.citation: J Biol Chem. 2007 Dec 21;282(51):37232-43
references.pmid: 17947239
references.citation: Nucleic Acids Res. 2000 Jan 1;28(1):235-42
references.pmid: 10592235
references.citation: Cell Mol Biol Lett. 2009;14(4):548-74
references.pmid: 19484198
references.citation: J Biol Chem. 2012 Jul 27;287(31):25954-63
references.pmid: 22692211
references.citation: Cell Signal. 2010 Aug;22(8):1185-92
references.pmid: 20227494
references.citation: Sci Am. 2000 Oct;283(4):82-7
references.pmid: 11011389
references.citation: J Mol Signal. 2012 Jul 16;7(1):9
references.pmid: 22800433
references.citation: J Biol Chem. 2003 Oct 24;278(43):42615-24
references.pmid: 12915405
references.citation: Mol Cell Proteomics. 2005 Jun;4(6):752-61
references.pmid: 15757999
references.citation: J Biol Chem. 2000 Dec 15;275(50):38973-80
references.pmid: 10978313
references.citation: Mol Cell Biol. 2003 Jul;23(13):4542-58
references.pmid: 12808096
references.citation: Chem Biol. 2013 Feb 21;20(2):146-59
references.pmid: 23438744
references.citation: Nucleic Acids Res. 2004 Jan 1;32(Database issue):D115-9
references.pmid: 14681372
references.citation: Cell Mol Life Sci. 2011 Mar;68(5):847-62
references.pmid: 20734105
references.citation: Nat Rev Cancer. 2009 Jan;9(1):28-39
references.pmid: 19104514
references.citation: Genes Dev. 2012 Jan 15;26(2):176-89
references.pmid: 22279049
references.citation: Front Biosci. 2008 May 01;13:4617-24
references.pmid: 18508533
references.citation: Mol Cell. 2011 Feb 18;41(4):445-57
references.pmid: 21329882
references.citation: Cell. 2002 May 3;109(3):275-82
references.pmid: 12015977
references.citation: Mol Biol Cell. 2003 Jun;14(6):2603-16
references.pmid: 12808055
references.citation: Microbiol Mol Biol Rev. 2011 Mar;75(1):50-83
references.pmid: 21372320
references.citation: J Biol Chem. 2006 Nov 17;281(46):35511-9
references.pmid: 16973613
references.citation: J Mol Biol. 1994 Jan 21;235(3):983-1002
references.pmid: 8289329
references.citation: PLoS Comput Biol. 2009 Oct;5(10):e1000528
references.pmid: 19816553
references.citation: World J Biol Chem. 2011 May 26;2(5):73-89
references.pmid: 21666810
references.citation: Cell Mol Life Sci. 2011 Jan;68(2):289-301
references.pmid: 20640477
references.citation: Proc Natl Acad Sci U S A. 2007 Apr 10;104(15):6353-8
references.pmid: 17395714
references.citation: Protein Sci. 2010 Jan;19(1):168-73
references.pmid: 19937655
references.citation: Protein Sci. 1993 Sep;2(9):1511-9
references.pmid: 8401235
references.citation: J Clin Microbiol. 1996 Nov;34(11):2679-84
references.pmid: 8897164
references.citation: J Cell Biochem. 2010 Aug 15;110(6):1420-9
references.pmid: 20506250
references.citation: Mol Cell Biol. 2002 Oct;22(20):6931-45
references.pmid: 12242275
references.citation: Cell Signal. 2007 Nov;19(11):2379-87
references.pmid: 17728103
references.citation: Mol Cancer Res. 2012 Jun;10(6):810-20
references.pmid: 22665523
references.citation: EMBO J. 1998 Jun 15;17(12):3372-84
references.pmid: 9628874
references.citation: J Mol Biol. 1990 Oct 5;215(3):403-10
references.pmid: 2231712