5ca1: Difference between revisions

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'''Unreleased structure'''
==Crystal structure of T2R-TTL-Nocodazole complex==
<StructureSection load='5ca1' size='340' side='right' caption='[[5ca1]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5ca1]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/ ] and [http://en.wikipedia.org/wiki/Sus_barbatus Sus barbatus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5CA1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5CA1 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NZO:NOCODAZOLE'>NZO</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5c8y|5c8y]], [[5ca0|5ca0]], [[5cb4|5cb4]]</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=5ca1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ca1 OCA], [http://pdbe.org/5ca1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ca1 RCSB], [http://www.ebi.ac.uk/pdbsum/5ca1 PDBsum]</span></td></tr>
</table>
== Function ==
[[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/TBB2_CHICK TBB2_CHICK]] 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.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Microtubules are dynamic assemblies of alphabeta-tubulin heterodimers and have been recognized as highly attractive targets for cancer chemotherapy. A broad range of agents bind to tubulin and interfere with microtubule assembly. Despite having a long history of characterization, colchicine binding site inhibitors (CBSIs) have not yet reached the commercial phase as anti-cancer drugs to date. We determined the structures of tubulin complexed with a set of structurally diverse CBSIs (lexibulin, nocodazole, plinabulin and tivantinib), among which nocodazole and tivantinib are both binary-function inhibitors targeting cancer-related kinases and microtubules simultaneously. High resolution structures revealed the detailed interactions between these ligands and tubulin. Our results showed that the binding modes of the CBSIs were different from previous docking models, highlighting the importance of crystal structure information in structure-based drug design. A real structure-based pharmacophore was proposed to rationalize key common interactions of the CBSIs at the colchicine domain. Our studies provide a solid structural basis for developing new anti-cancer agents for the colchicine binding site. DATABASE: The atomic coordinates and structure factors for tubulin complexed with lexibulin, nocodazole, plinabulin and tivantinib have been deposited in the Protein Data Bank under accession codes 5CA0, 5CA1, 5C8Y and 5CB4, respectively.


The entry 5ca1 is ON HOLD  until Paper Publication
Structures of a diverse set of colchicine binding site inhibitors in complex with tubulin provide a rationale for drug discovery.,Wang Y, Zhang H, Gigant B, Yu Y, Wu Y, Chen X, Lai Q, Yang Z, Chen Q, Yang J FEBS J. 2016 Jan;283(1):102-11. doi: 10.1111/febs.13555. Epub 2015 Nov 4. PMID:26462166<ref>PMID:26462166</ref>


Authors: Wang, Y., Yu, Y., Chen, Q., Yang, J.
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 
</div>
Description: Crystal structure of T2R-TTL-Nocodazole complex
<div class="pdbe-citations 5ca1" style="background-color:#fffaf0;"></div>
[[Category: Unreleased Structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Sus barbatus]]
[[Category: Chen, Q]]
[[Category: Wang, Y]]
[[Category: Wang, Y]]
[[Category: Yang, J]]
[[Category: Yang, J]]
[[Category: Yu, Y]]
[[Category: Yu, Y]]
[[Category: Chen, Q]]
[[Category: Complex]]
[[Category: Inhibitor]]
[[Category: Structural protein]]
[[Category: Tubulin]]

Revision as of 21:24, 27 January 2016

Crystal structure of T2R-TTL-Nocodazole complexCrystal structure of T2R-TTL-Nocodazole complex

Structural highlights

5ca1 is a 6 chain structure with sequence from [1] and Sus barbatus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:, , , , , , ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum

Function

[STMN4_RAT] Exhibits microtubule-destabilizing activity.[1] [2] [3] [TBB2_CHICK] 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.

Publication Abstract from PubMed

Microtubules are dynamic assemblies of alphabeta-tubulin heterodimers and have been recognized as highly attractive targets for cancer chemotherapy. A broad range of agents bind to tubulin and interfere with microtubule assembly. Despite having a long history of characterization, colchicine binding site inhibitors (CBSIs) have not yet reached the commercial phase as anti-cancer drugs to date. We determined the structures of tubulin complexed with a set of structurally diverse CBSIs (lexibulin, nocodazole, plinabulin and tivantinib), among which nocodazole and tivantinib are both binary-function inhibitors targeting cancer-related kinases and microtubules simultaneously. High resolution structures revealed the detailed interactions between these ligands and tubulin. Our results showed that the binding modes of the CBSIs were different from previous docking models, highlighting the importance of crystal structure information in structure-based drug design. A real structure-based pharmacophore was proposed to rationalize key common interactions of the CBSIs at the colchicine domain. Our studies provide a solid structural basis for developing new anti-cancer agents for the colchicine binding site. DATABASE: The atomic coordinates and structure factors for tubulin complexed with lexibulin, nocodazole, plinabulin and tivantinib have been deposited in the Protein Data Bank under accession codes 5CA0, 5CA1, 5C8Y and 5CB4, respectively.

Structures of a diverse set of colchicine binding site inhibitors in complex with tubulin provide a rationale for drug discovery.,Wang Y, Zhang H, Gigant B, Yu Y, Wu Y, Chen X, Lai Q, Yang Z, Chen Q, Yang J FEBS J. 2016 Jan;283(1):102-11. doi: 10.1111/febs.13555. Epub 2015 Nov 4. PMID:26462166[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ Wang Y, Zhang H, Gigant B, Yu Y, Wu Y, Chen X, Lai Q, Yang Z, Chen Q, Yang J. Structures of a diverse set of colchicine binding site inhibitors in complex with tubulin provide a rationale for drug discovery. FEBS J. 2016 Jan;283(1):102-11. doi: 10.1111/febs.13555. Epub 2015 Nov 4. PMID:26462166 doi:http://dx.doi.org/10.1111/febs.13555

5ca1, resolution 2.40Å

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