title: Structural basis for the inhibition of Polo-like kinase 1.
abstract: Polo-like kinase 1 (PLK1) is a master regulator of mitosis and is considered a potential drug target for cancer therapy. PLK1 is characterized by an N-terminal kinase domain (KD) and a C-terminal Polo-box domain (PBD). The KD and PBD are mutually inhibited, but the molecular mechanisms of the autoinhibition remain unclear. Here we report the 2.3-Å crystal structure of the complex of the Danio rerio KD and PBD together with a PBD-binding motif of Drosophila melanogaster microtubule-associated protein 205 (Map205(PBM)). The structure reveals that the PBD binds and rigidifies the hinge region of the KD in a distinct conformation from that of the phosphopeptide-bound PBD. This structure provides a framework for understanding the autoinhibitory mechanisms of PLK1 and also sheds light on the activation mechanisms of PLK1 by phosphorylation or phosphopeptide binding.
authors.affiliation: Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.forename: Chen
authors.initials: C
authors.lastname: Shen
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Junmin
authors.initials: J
authors.lastname: Quan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D018360:Crystallography, X-Ray; D029721:Drosophila Proteins / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000737:chemistry* / Q000235:genetics; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000737:chemistry / Q000235:genetics; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D029961:Zebrafish Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D008869:Microtubule-Associated Proteins; D046912:Multiprotein Complexes; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D029961:Zebrafish Proteins; D000097869:Polo-Like Kinase 1; C505941:Map205 protein, Drosophila; C072004:polo protein, Drosophila
references.citation: Biochemistry. 2007 May 22;46(20):5960-71
references.pmid: 17461553
references.citation: Cell. 2011 Sep 2;146(5):732-45
references.pmid: 21884935
references.citation: Cell. 2003 Oct 3;115(1):83-95
references.pmid: 14532005
references.citation: Mol Biol Cell. 2006 Jan;17(1):448-59
references.pmid: 16267267
references.citation: Cell. 2007 May 18;129(4):735-46
references.pmid: 17512407
references.citation: Nat Chem Biol. 2011 Jul 17;7(9):595-601
references.pmid: 21765407
references.citation: J Appl Crystallogr. 2007 Aug 1;40(Pt 4):658-674
references.pmid: 19461840
references.citation: Mol Cell Biol. 1999 Dec;19(12):8625-32
references.pmid: 10567586
references.citation: Cell Cycle. 2006 Apr;5(8):853-64
references.pmid: 16627997
references.citation: Nat Rev Cancer. 2006 Apr;6(4):321-30
references.pmid: 16557283
references.citation: Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):235-42
references.pmid: 21460441
references.citation: Anal Biochem. 2008 Dec 15;383(2):205-9
references.pmid: 18793607
references.citation: Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9301-6
references.pmid: 9689075
references.citation: Methods Enzymol. 1983;99:3-6
references.pmid: 6316096
references.citation: J Biol Chem. 2002 Aug 30;277(35):32282-93
references.pmid: 12034729
references.citation: Acta Crystallogr D Biol Crystallogr. 1997 May 1;53(Pt 3):240-55
references.pmid: 15299926
references.citation: Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14542-6
references.pmid: 19706541
references.citation: J Cell Biol. 2004 Jan 19;164(2):233-41
references.pmid: 14734534
references.citation: Nat Rev Drug Discov. 2010 Aug;9(8):643-60
references.pmid: 20671765
references.citation: Biochemistry. 1995 Nov 14;34(45):14843-51
references.pmid: 7578094
references.citation: Oncologist. 2009 Jun;14(6):559-70
references.pmid: 19474163
references.citation: Nat Rev Mol Cell Biol. 2004 Jun;5(6):429-40
references.pmid: 15173822
references.citation: Oncogene. 2005 Jan 10;24(2):267-76
references.pmid: 15640842
references.citation: Nat Chem Biol. 2010 Nov;6(11):821-8
references.pmid: 20890288
references.citation: Mol Cell Biol. 2005 Mar;25(5):2031-44
references.pmid: 15713655
references.citation: Science. 2008 Jun 20;320(5883):1655-8
references.pmid: 18566290
references.citation: Cell. 2007 Jun 15;129(6):1177-87
references.pmid: 17574028
references.citation: Nature. 1997 Feb 13;385(6617):602-9
references.pmid: 9024658
references.citation: Nature. 2008 Sep 4;455(7209):119-23
references.pmid: 18615013
references.citation: Nat Cell Biol. 2006 Feb;8(2):180-7
references.pmid: 16378098
references.citation: J Biol Chem. 2002 Nov 15;277(46):44115-20
references.pmid: 12207013
references.citation: Protein Sci. 1997 Dec;6(12):2561-7
references.pmid: 9416605
references.citation: Cell Mol Life Sci. 2010 Jun;67(12):1957-70
references.pmid: 20148280
references.citation: Cell. 2002 May 3;109(3):275-82
references.pmid: 12015977
references.citation: Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32
references.pmid: 15572765
references.citation: EMBO J. 2003 Nov 3;22(21):5757-68
references.pmid: 14592974
references.citation: Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):213-21
references.pmid: 20124702
references.citation: Cell. 2003 Mar 21;112(6):859-71
references.pmid: 12654251
references.citation: Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):1984-9
references.pmid: 11854496
references.citation: Mol Cell. 2006 Nov 3;24(3):409-22
references.pmid: 17081991
references.citation: Cell. 2007 Nov 30;131(5):847-60
references.pmid: 18045532
references.citation: Nature. 1997 Feb 13;385(6617):595-602
references.pmid: 9024657
references.citation: Oncogene. 2005 Jan 10;24(2):248-59
references.pmid: 15640840
references.citation: Angew Chem Int Ed Engl. 2011 Apr 18;50(17):4003-6
references.pmid: 21472932
references.citation: Mol Biol Cell. 2006 Aug;17(8):3705-16
references.pmid: 16760428
references.citation: Science. 2003 Feb 21;299(5610):1228-31
references.pmid: 12595692
references.citation: Biochemistry. 2008 Mar 25;47(12):3688-96
references.pmid: 18298087
references.citation: Dev Cell. 2008 May;14(5):646-59
references.pmid: 18477449
references.citation: Genes Dev. 2008 Oct 1;22(19):2707-20
references.pmid: 18832073
references.citation: Acta Crystallogr D Biol Crystallogr. 2008 Sep;64(Pt 9):909-18
references.pmid: 18703838
references.citation: Nat Struct Mol Biol. 2009 Aug;16(8):876-82
references.pmid: 19597481
references.citation: Nat Rev Mol Cell Biol. 2009 Apr;10(4):265-75
references.pmid: 19305416
references.citation: Biochem Biophys Res Commun. 1997 Oct 20;239(2):377-85
references.pmid: 9344838
references.citation: J Cell Biol. 2007 Nov 19;179(4):611-7
references.pmid: 17998400