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==CRYSTAL STRUCTURE OF TUBULIN-STATHMIN-TTL-HTI286 COMPLEX==
==CRYSTAL STRUCTURE OF TUBULIN-STATHMIN-TTL-HTI286 COMPLEX==
<StructureSection load='4zi7' size='340' side='right' caption='[[4zi7]], [[Resolution|resolution]] 2.51&Aring;' scene=''>
<StructureSection load='4zi7' size='340' side='right'caption='[[4zi7]], [[Resolution|resolution]] 2.51&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4zi7]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/ ] and [http://en.wikipedia.org/wiki/Sus_scrofa Sus scrofa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZI7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ZI7 FirstGlance]. <br>
<table><tr><td colspan='2'>[[4zi7]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Gallus_gallus Gallus gallus], [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus] and [https://en.wikipedia.org/wiki/Sus_scrofa Sus scrofa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZI7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ZI7 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4SL:N,BETA,BETA-TRIMETHYL-L-PHENYLALANYL-N-[(3S,4Z)-5-CARBOXY-2-METHYLHEX-4-EN-3-YL]-N,3-DIMETHYL-L-VALINAMIDE'>4SL</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]] 2.51&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4zhq|4zhq]], [[4zol|4zol]], [[5bmv|5bmv]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4SL:N,BETA,BETA-TRIMETHYL-L-PHENYLALANYL-N-[(3S,4Z)-5-CARBOXY-2-METHYLHEX-4-EN-3-YL]-N,3-DIMETHYL-L-VALINAMIDE'>4SL</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=4zi7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zi7 OCA], [http://pdbe.org/4zi7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4zi7 RCSB], [http://www.ebi.ac.uk/pdbsum/4zi7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4zi7 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=4zi7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zi7 OCA], [https://pdbe.org/4zi7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4zi7 RCSB], [https://www.ebi.ac.uk/pdbsum/4zi7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4zi7 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/TBA1B_PIG TBA1B_PIG]] 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/TBB_PIG TBB_PIG]] 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.
[https://www.uniprot.org/uniprot/TBA1B_PIG TBA1B_PIG] 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 ==
Antibody-drug conjugates (ADCs) have achieved great success in cancer therapy in recent years. Some peptidyl microtubule inhibitors consisting of natural and unnatural amino acids, such as monomethyl auristatin E (MMAE) and F (MMAF), are extremely cytotoxic and have been used as a payload in ADCs. However, their precise molecular interaction with tubulin and microtubules remains unclear. We determined the crystal structures of tubulin in complex with three ultra-potent peptidyl microtubule inhibitors [MMAE, taltobulin (HTI- 286), and tubulysin M] at 2.5 A. Our data showed that the three peptides bound to the vinca domain and shared a common and key pharmacophore containing two consecutive hydrophobic groups (Val, Ile-like side chain). These groups protruded in opposite directions into hydrophobic pockets on the tubulin beta and alpha subunits. Nitrogen and oxygen atoms from the same backbone formed hydrogen bonds with Asn329 from the alpha subunit and Asp179 from the beta subunit in a direction normal to the surface formed by the aforementioned hydrophobic groups. In addition, our crystal structure data indicated that tubulysin M bound to the beta subunit alone, providing a structural explanation for its higher affinity. We also compared the conformations of two representative structurally different vinca domain compounds, ustiloxin D and vinblastine, with those of the aforementioned peptidyl ligands, and found that they shared a similar pharmacophore. Our findings lay a foundation for the rational design of novel vinca domain ligands and may facilitate the development of microtubule inhibitors with high specificity, affinity, and efficiency as payloads for ADCs in cancer therapy.


Structural Insights into the Pharmacophore of Vinca Domain Inhibitors of Microtubules.,Wang Y, Benz FW, Wu Y, Wang Q, Chen Y, Chen X, Li H, Zhang Y, Zhang R, Yang J Mol Pharmacol. 2016 Feb;89(2):233-42. doi: 10.1124/mol.115.100149. Epub 2015 Dec , 9. PMID:26660762<ref>PMID:26660762</ref>
==See Also==
 
*[[Stathmin-4 3D structures|Stathmin-4 3D structures]]
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
*[[Tubulin 3D Structures|Tubulin 3D Structures]]
</div>
<div class="pdbe-citations 4zi7" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Gallus gallus]]
[[Category: Large Structures]]
[[Category: Rattus norvegicus]]
[[Category: Sus scrofa]]
[[Category: Sus scrofa]]
[[Category: Wang, Y]]
[[Category: Wang Y]]
[[Category: Zhang, R]]
[[Category: Zhang R]]
[[Category: Structural protein-inhibitor complex]]

Latest revision as of 12:04, 20 March 2024

CRYSTAL STRUCTURE OF TUBULIN-STATHMIN-TTL-HTI286 COMPLEXCRYSTAL STRUCTURE OF TUBULIN-STATHMIN-TTL-HTI286 COMPLEX

Structural highlights

4zi7 is a 6 chain structure with sequence from Gallus gallus, Rattus norvegicus and Sus scrofa. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.51Å
Ligands:, , , , , , ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

TBA1B_PIG 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.

See Also

4zi7, resolution 2.51Å

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