4tv9

From Proteopedia

(Difference between revisions)

Revision as of 07:02, 5 August 2016

Tubulin-PM060184 complex

Structural highlights

4tv9 is a 6 chain structure with sequence from [1] and Bos taurus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , , , , , ,
Related:	4i4t, 4i50, 4i55, 4ihj, 4iij, 4o4h, 4o4i, 4o4j, 4o4l, 4o2a, 4o2b, 4tv8
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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

Publication Abstract from PubMed

The recent success of antibody-drug conjugates (ADCs) in the treatment of cancer has led to a revived interest in microtubule-destabilizing agents. Here, we determined the high-resolution crystal structure of the complex between tubulin and maytansine, which is part of an ADC that is approved by the US Food and Drug Administration (FDA) for the treatment of advanced breast cancer. We found that the drug binds to a site on beta-tubulin that is distinct from the vinca domain and that blocks the formation of longitudinal tubulin interactions in microtubules. We also solved crystal structures of tubulin in complex with both a variant of rhizoxin and the phase 1 drug PM060184. Consistent with biochemical and mutagenesis data, we found that the two compounds bound to the same site as maytansine and that the structures revealed a common pharmacophore for the three ligands. Our results delineate a distinct molecular mechanism of action for the inhibition of microtubule assembly by clinically relevant agents. They further provide a structural basis for the rational design of potent microtubule-destabilizing agents, thus opening opportunities for the development of next-generation ADCs for the treatment of cancer.

A new tubulin-binding site and pharmacophore for microtubule-destabilizing anticancer drugs.,Prota AE, Bargsten K, Diaz JF, Marsh M, Cuevas C, Liniger M, Neuhaus C, Andreu JM, Altmann KH, Steinmetz MO Proc Natl Acad Sci U S A. 2014 Aug 11. pii: 201408124. PMID:25114240^[4]

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

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
↑ Prota AE, Bargsten K, Diaz JF, Marsh M, Cuevas C, Liniger M, Neuhaus C, Andreu JM, Altmann KH, Steinmetz MO. A new tubulin-binding site and pharmacophore for microtubule-destabilizing anticancer drugs. Proc Natl Acad Sci U S A. 2014 Aug 11. pii: 201408124. PMID:25114240 doi:http://dx.doi.org/10.1073/pnas.1408124111

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4tv9"

@@ Line 1: / Line 1: @@
 ==Tubulin-PM060184 complex==
 <StructureSection load='4tv9' size='340' side='right' caption='[[4tv9]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
@@ Line 5: / Line 6: @@
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3H4:(1Z,4S,6Z)-1-[(N-{(2Z,4Z,6E,8S)-8-[(2S)-5-METHOXY-6-OXO-3,6-DIHYDRO-2H-PYRAN-2-YL]-6-METHYLNONA-2,4,6-TRIENOYL}-3-METHYL-L-VALYL)AMINO]OCTA-1,6-DIEN-4-YL+CARBAMATE'>3H4</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=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4i4t|4i4t]], [[4i50|4i50]], [[4i55|4i55]], [[4ihj|4ihj]], [[4iij|4iij]], [[4o4h|4o4h]], [[4o4i|4o4i]], [[4o4j|4o4j]], [[4o4l|4o4l]], [[4o2a|4o2a]], [[4o2b|4o2b]], [[4tv8|4tv8]]</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=4tv9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4tv9 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4tv9 RCSB], [http://www.ebi.ac.uk/pdbsum/4tv9 PDBsum]</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=4tv9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4tv9 OCA], [http://pdbe.org/4tv9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4tv9 RCSB], [http://www.ebi.ac.uk/pdbsum/4tv9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4tv9 ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 17: / Line 18: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4tv9" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Tubulin|Tubulin]]
 == References ==
 <references/>

4tv9

From Proteopedia

Revision as of 07:02, 5 August 2016

Tubulin-PM060184 complex

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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