4O4J: Tubulin-peloruside A Complex

Citation:
Abstract
Laulimalide and peloruside A are microtubule-stabilizing agents (MSAs), the mechanism of action on microtubules of which is poorly defined. Here, using X-ray crystallography it is shown that laulimalide and peloruside A bind to a unique non-taxane site on beta-tubulin and use their respective macrolide core structures to interact with a second tubulin dimer across protofilaments. At the same time, they allosterically stabilize the taxane-site M-loop that establishes lateral tubulin contacts in microtubules. Structures of ternary complexes of tubulin with laulimalide/peloruside A and epothilone A are also solved, and a crosstalk between the laulimalide/peloruside and taxane sites via the M-loop of beta-tubulin is found. Together, the data define the mechanism of action of laulimalide and peloruside A on tubulin and microtubules. The data further provide a structural framework for understanding the synergy observed between two classes of MSAs in tubulin assembly and the inhibition of cancer cell growth.
PDB ID: 4O4JDownload
MMDB ID: 118658
PDB Deposition Date: 2013/12/18
Updated in MMDB: 2014/03
Experimental Method:
x-ray diffraction
Resolution: 2.2  Å
Source Organism:
Rattus norvegicus
Similar Structures:
Biological Unit for 4O4J: hexameric; determined by author
Molecular Components in 4O4J
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 (13 molecules)
1
2
2
4
3
1
4
1
5
2
6
2
7
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
.