4TV8: Tubulin-maytansine Complex

Citation:
Abstract
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.
PDB ID: 4TV8Download
MMDB ID: 122774
PDB Deposition Date: 2014/6/26
Updated in MMDB: 2014/08
Experimental Method:
x-ray diffraction
Resolution: 2.1  Å
Source Organism:
Rattus norvegicus
Similar Structures:
Biological Unit for 4TV8: hexameric; determined by author and by software (PISA)
Molecular Components in 4TV8
Label Count Molecule
Proteins (6 molecules)
2
Tubulin Alpha-1b Chain(Gene symbol: TUBA1A)
Molecule annotation
2
Tubulin Beta-2b Chain(Gene symbol: TUBB2B)
Molecule annotation
1
Stathmin-4(Gene symbol: Stmn4)
Molecule annotation
1
Tubulin-tyrosine Ligase
Molecule annotation
Chemicals (17 molecules)
1
2
2
4
3
4
4
2
5
2
6
1
7
1
8
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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