title: Structural insight into the inhibition of tubulin by vinca domain peptide ligands.
abstract: The tubulin vinca domain is the target of widely different microtubule inhibitors that interfere with the binding of vinblastine. Although all these ligands inhibit the hydrolysis of GTP, they affect nucleotide exchange to variable extents. The structures of two vinca domain antimitotic peptides--phomopsin A and soblidotin (a dolastatin 10 analogue)--bound to tubulin in a complex with a stathmin-like domain show that their sites partly overlap with that of vinblastine and extend the definition of the vinca domain. The structural data, together with the biochemical results from the ligands we studied, highlight two main contributors in nucleotide exchange: the flexibility of the tubulin subunits' arrangement at their interfaces and the residues in the carboxy-terminal part of the beta-tubulin H6-H7 loop. The structures also highlight common features of the mechanisms by which vinca domain ligands favour curved tubulin assemblies and destabilize microtubules.
authors.affiliation: Laboratoire d'Enzymologie et Biochimie Structurales, CNRS, Bat. 34, 1 avenue de la Terrasse, 91198 Gif-sur-Yvette, France.
authors.forename: Anthony
authors.initials: A
authors.lastname: Cormier
authors.forename: Matthieu
authors.initials: M
authors.lastname: Marchand
authors.forename: Raimond B G
authors.initials: RB
authors.lastname: Ravelli
authors.forename: Marcel
authors.initials: M
authors.lastname: Knossow
authors.forename: Benoît
authors.initials: B
authors.lastname: Gigant
mesh_terms: D008024:Ligands; D008870:Microtubules / Q000378:metabolism; D008958:Models, Molecular; D009183:Mycotoxins / Q000378:metabolism; D009842:Oligopeptides / Q000378:metabolism; D017434:Protein Structure, Tertiary; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D014747:Vinblastine / Q000378:metabolism
chemical_list: D008024:Ligands; D009183:Mycotoxins; D009842:Oligopeptides; D014404:Tubulin; D014747:Vinblastine; C035753:phomopsin; C105791:soblidotin
references.citation: Proc Natl Acad Sci U S A. 1984 Feb;81(3):771-5
references.pmid: 6583675
references.citation: Methods Mol Med. 2007;137:235-43
references.pmid: 18085233
references.citation: Cancer Sci. 2007 Apr;98(4):598-604
references.pmid: 17284247
references.citation: Biochem Pharmacol. 1993 Apr 6;45(7):1503-15
references.pmid: 8471072
references.citation: Acta Crystallogr D Biol Crystallogr. 2001 Jan;57(Pt 1):122-33
references.pmid: 11134934
references.citation: Nature. 1984 Nov 15-21;312(5991):237-42
references.pmid: 6504138
references.citation: Biochemistry. 1999 Oct 26;38(43):14302-10
references.pmid: 10572005
references.citation: Nature. 2004 Mar 11;428(6979):198-202
references.pmid: 15014504
references.citation: J Biol Chem. 1979 Nov 25;254(22):11696-702
references.pmid: 227875
references.citation: Cell. 2000 Sep 15;102(6):809-16
references.pmid: 11030624
references.citation: J Biol Chem. 1977 May 10;252(9):2891-9
references.pmid: 16006
references.citation: Biochem Pharmacol. 1990 Oct 15;40(8):1859-64
references.pmid: 2242019
references.citation: Biochemistry. 2007 Sep 18;46(37):10595-602
references.pmid: 17711308
references.citation: EMBO J. 1988 Feb;7(2):357-65
references.pmid: 3366117
references.citation: J Biol Chem. 1990 Oct 5;265(28):17141-9
references.pmid: 2211617
references.citation: Biochemistry. 1982 Jun 8;21(12):2996-3006
references.pmid: 7104309
references.citation: J Biol Chem. 2004 Jul 16;279(29):30731-40
references.pmid: 15123603
references.citation: Jpn J Cancer Res. 2000 Jul;91(7):737-47
references.pmid: 10920282
references.citation: Proc Natl Acad Sci U S A. 1987 Aug;84(15):5257-61
references.pmid: 3474652
references.citation: Biochemistry. 2000 Oct 10;39(40):12295-302
references.pmid: 11015208
references.citation: Cell. 1999 Jan 8;96(1):79-88
references.pmid: 9989499
references.citation: J Antibiot (Tokyo). 1998 Apr;51(4):418-22
references.pmid: 9630863
references.citation: Pharmacol Ther. 1992;55(1):31-51
references.pmid: 1287674
references.citation: J Am Chem Soc. 2008 Feb 20;130(7):2351-64
references.pmid: 18229928
references.citation: Nature. 2005 May 26;435(7041):519-22
references.pmid: 15917812
references.citation: Nat Struct Biol. 1998 Jun;5(6):451-8
references.pmid: 9628483
references.citation: Arch Biochem Biophys. 1980 Aug;203(1):404-11
references.pmid: 7406508