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| | ==Crystal structure of tubulin-stathmin-TTL-Compound Z1 complex== | | ==Crystal structure of tubulin-stathmin-TTL-Compound Z1 complex== |
| - | <StructureSection load='5xaf' size='340' side='right' caption='[[5xaf]], [[Resolution|resolution]] 2.55Å' scene=''> | + | <StructureSection load='5xaf' size='340' side='right'caption='[[5xaf]], [[Resolution|resolution]] 2.55Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5xaf]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Bovin Bovin], [http://en.wikipedia.org/wiki/Buffalo_rat Buffalo rat] and [http://en.wikipedia.org/wiki/Chick Chick]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5XAF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5XAF FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5xaf]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus], [https://en.wikipedia.org/wiki/Gallus_gallus Gallus gallus] and [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5XAF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5XAF FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=84F:(3S,4R)-4-(3-hydroxy-4-methoxyphenyl)-3-methyl-1-(3,4,5-trimethoxyphenyl)azetidin-2-one'>84F</scene>, <scene name='pdbligand=ACP:PHOSPHOMETHYLPHOSPHONIC+ACID+ADENYLATE+ESTER'>ACP</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=GTP:GUANOSINE-5-TRIPHOSPHATE'>GTP</scene>, <scene name='pdbligand=IMD:IMIDAZOLE'>IMD</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.551Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5xag|5xag]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=84F:(3S,4R)-4-(3-hydroxy-4-methoxyphenyl)-3-methyl-1-(3,4,5-trimethoxyphenyl)azetidin-2-one'>84F</scene>, <scene name='pdbligand=ACP:PHOSPHOMETHYLPHOSPHONIC+ACID+ADENYLATE+ESTER'>ACP</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=GTP:GUANOSINE-5-TRIPHOSPHATE'>GTP</scene>, <scene name='pdbligand=IMD:IMIDAZOLE'>IMD</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TUBB2B ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9913 BOVIN]), Stmn4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Buffalo rat]), TTL ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9031 CHICK])</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5xaf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5xaf OCA], [https://pdbe.org/5xaf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5xaf RCSB], [https://www.ebi.ac.uk/pdbsum/5xaf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5xaf ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5xaf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5xaf OCA], [http://pdbe.org/5xaf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5xaf RCSB], [http://www.ebi.ac.uk/pdbsum/5xaf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5xaf ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/TBA1B_BOVIN TBA1B_BOVIN]] Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain. [[http://www.uniprot.org/uniprot/STMN4_RAT STMN4_RAT]] Exhibits microtubule-destabilizing activity.<ref>PMID:15039434</ref> <ref>PMID:12111843</ref> <ref>PMID:15014504</ref> [[http://www.uniprot.org/uniprot/TBB2B_BOVIN TBB2B_BOVIN]] Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain (By similarity). | + | [https://www.uniprot.org/uniprot/STMN4_RAT STMN4_RAT] Exhibits microtubule-destabilizing activity.<ref>PMID:15039434</ref> <ref>PMID:12111843</ref> <ref>PMID:15014504</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5xaf" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5xaf" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Stathmin-4 3D structures|Stathmin-4 3D structures]] |
| | + | *[[Tubulin 3D Structures|Tubulin 3D Structures]] |
| | + | *[[Tubulin tyrosine ligase|Tubulin tyrosine ligase]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Bovin]] | + | [[Category: Bos taurus]] |
| - | [[Category: Buffalo rat]] | + | [[Category: Gallus gallus]] |
| - | [[Category: Chick]] | + | [[Category: Large Structures]] |
| - | [[Category: Luo, C]] | + | [[Category: Rattus norvegicus]] |
| - | [[Category: Wang, Y]] | + | [[Category: Luo C]] |
| - | [[Category: Zhang, H]] | + | [[Category: Wang Y]] |
| - | [[Category: Structural protein]] | + | [[Category: Zhang H]] |
| - | [[Category: Tubulin]]
| + | |
| Structural highlights
5xaf is a 6 chain structure with sequence from Bos taurus, Gallus gallus and Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 2.551Å |
| Ligands: | , , , , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
STMN4_RAT Exhibits microtubule-destabilizing activity.[1] [2] [3]
Publication Abstract from PubMed
A diverse of chiral beta-lactam bridged analogues of combretastatin A-4 (CA-4), 3-substituted 1,4-diaryl-2-azetidinones, were asymmetrically synthesized and biologically evaluated, leading to identify a number of potent anti-proliferative compounds represented by 14b and 14c with IC50 values of 0.001-0.021 muM, against four human cancer cell lines (A2780, Hela, SKOV-3 and MDA-MB-231). Structure-activity relationship (SAR) studies on all stereoisomers of 14b and 14c revealed that the absolute configurations of the chiral centers at 3- and 4-position were critically important for the activity and generally a trans configuration between the "A" and "B" rings is optimal. In addition, 14b and 14c displayed less cytotoxicity on normal human oviduct epithelial cells than malignant cells indicating good selectivity in vitro. Further biochemical evaluation and cocrystal structures with tubulin demonstrated that both compounds disrupted tubulin polymerization through interacting at the colchicine-binding site, suppressed angiogenesis in vitro and in vivo, blocked cell cycle progression at mitotic phase and induced cellular apoptosis. The in vivo assays verified that both compounds inhibited xenograft tumor growth in nude mice with acceptable therapeutic window, showing promising potentials for further clinical development.
Design, synthesis, biological evaluation and cocrystal structures with tubulin of chiral beta-lactam bridged combretastatin A-4 analogues as potent antitumor agents.,Zhou P, Liang Y, Zhang H, Jiang H, Feng K, Xu P, Wang J, Wang X, Ding K, Luo C, Liu M, Wang Y Eur J Med Chem. 2017 Dec 7;144:817-842. doi: 10.1016/j.ejmech.2017.12.004. PMID:29306206[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Nakao C, Itoh TJ, Hotani H, Mori N. Modulation of the stathmin-like microtubule destabilizing activity of RB3, a neuron-specific member of the SCG10 family, by its N-terminal domain. J Biol Chem. 2004 May 28;279(22):23014-21. Epub 2004 Mar 22. PMID:15039434 doi:http://dx.doi.org/10.1074/jbc.M313693200
- ↑ Gavet O, El Messari S, Ozon S, Sobel A. Regulation and subcellular localization of the microtubule-destabilizing stathmin family phosphoproteins in cortical neurons. J Neurosci Res. 2002 Jun 1;68(5):535-50. PMID:12111843 doi:http://dx.doi.org/10.1002/jnr.10234
- ↑ Ravelli RB, Gigant B, Curmi PA, Jourdain I, Lachkar S, Sobel A, Knossow M. Insight into tubulin regulation from a complex with colchicine and a stathmin-like domain. Nature. 2004 Mar 11;428(6979):198-202. PMID:15014504 doi:http://dx.doi.org/10.1038/nature02393
- ↑ Zhou P, Liang Y, Zhang H, Jiang H, Feng K, Xu P, Wang J, Wang X, Ding K, Luo C, Liu M, Wang Y. Design, synthesis, biological evaluation and cocrystal structures with tubulin of chiral beta-lactam bridged combretastatin A-4 analogues as potent antitumor agents. Eur J Med Chem. 2017 Dec 7;144:817-842. doi: 10.1016/j.ejmech.2017.12.004. PMID:29306206 doi:http://dx.doi.org/10.1016/j.ejmech.2017.12.004
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