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4tv8

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Tubulin-Maytansine complex

Structural highlights

4tv8 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 2.103Å
Ligands:	, , , , , , ,
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.

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^[1]

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

References

↑ 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/4tv8"

@@ Line 1: / Line 1: @@
 ==Tubulin-Maytansine complex==
-<StructureSection load='4tv8' size='340' side='right' caption='[[4tv8]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
+<StructureSection load='4tv8' size='340' side='right'caption='[[4tv8]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4tv8]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/ ] and [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4TV8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4TV8 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4tv8]] 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=4TV8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4TV8 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3GT:(3BETA,4BETA,5BETA,10BETA,11E,13E)-MAYTANSINE'>3GT</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>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.103&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4tv9|4tv9]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3GT:(3BETA,4BETA,5BETA,10BETA,11E,13E)-MAYTANSINE'>3GT</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='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=4tv8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4tv8 OCA], [http://pdbe.org/4tv8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4tv8 RCSB], [http://www.ebi.ac.uk/pdbsum/4tv8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4tv8 ProSAT]</span></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=4tv8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4tv8 OCA], [https://pdbe.org/4tv8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4tv8 RCSB], [https://www.ebi.ac.uk/pdbsum/4tv8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4tv8 ProSAT]</span></td></tr>
 </table>
 == 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/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.
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 21: / Line 21: @@
 ==See Also==
-*[[Stathmin|Stathmin]]
+*[[Stathmin-4 3D structures|Stathmin-4 3D structures]]
-*[[Tubulin|Tubulin]]
+*[[Tubulin 3D Structures|Tubulin 3D Structures]]
 *[[Tubulin tyrosine ligase|Tubulin tyrosine ligase]]
 == References ==
@@ Line 29: / Line 29: @@
 </StructureSection>
 [[Category: Bos taurus]]
-[[Category: Altmann, K H]]
+[[Category: Gallus gallus]]
-[[Category: Andreu, J M]]
+[[Category: Large Structures]]
-[[Category: Bargsten, K]]
+[[Category: Rattus norvegicus]]
-[[Category: Cuevas, C]]
+[[Category: Altmann KH]]
-[[Category: Diaz, J F]]
+[[Category: Andreu JM]]
-[[Category: Liniger, M]]
+[[Category: Bargsten K]]
-[[Category: Marsh, M]]
+[[Category: Cuevas C]]
-[[Category: Neuhaus, C]]
+[[Category: Diaz JF]]
-[[Category: Prota, A E]]
+[[Category: Liniger M]]
-[[Category: Steinmetz, M O]]
+[[Category: Marsh M]]
-[[Category: Cell cycle]]
+[[Category: Neuhaus C]]
-[[Category: Cytoskeleton]]
+[[Category: Prota AE]]
-[[Category: Microtubule]]
+[[Category: Steinmetz MO]]
-[[Category: Tubulin fold]]

4tv8

From Proteopedia

Current revision

Tubulin-Maytansine complex

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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