4ZHQ: Crystal Structure Of Tubulin-stathmin-ttl-mmae Complex

Citation:
Abstract
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.
PDB ID: 4ZHQDownload
MMDB ID: 141217
PDB Deposition Date: 2015/4/26
Updated in MMDB: 2016/08
Experimental Method:
x-ray diffraction
Resolution: 2.55  Å
Source Organism:
Rattus norvegicus
Similar Structures:
Biological Unit for 4ZHQ: hexameric; determined by author
Molecular Components in 4ZHQ
Label Count Molecule
Proteins (6 molecules)
2
Tubulin Alpha-1b Chain(Gene symbol: TUBA1B)
Molecule annotation
2
Tubulin Beta Chain
Molecule annotation
1
Stathmin-4(Gene symbol: Stmn4)
Molecule annotation
1
Tubulin-tyrosine Ligase
Molecule annotation
Chemicals (23 molecules)
1
2
2
4
3
3
4
8
5
2
6
2
7
1
8
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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