4O4I

Tubulin-Laulimalide-Epothilone A complex

Summary for 4O4I

• Entry DOI: 10.2210/pdb4o4i/pdb
• Related: 4O4H 4O4J 4O4L
• Descriptor: Tubulin alpha-1B chain, Laulimalide, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, ... (13 entities in total)
• Functional Keywords: alpha-tubulin, beta-tubulin, ligase, gtpase, microtubule, stathmin, laulimalide, epothilone a, cell cycle, tubulin fold, cytoskeleton, cell cycle-inhibitor complex, cell cycle/inhibitor
• Biological source: Rattus norvegicus (rat); More
• Cellular location: Cytoplasm, cytoskeleton: P81947; Cytoplasm, cytoskeleton (By similarity): Q6B856; Golgi apparatus: P63043
• Total number of polymer chains: 6
• Total formula weight: 266032.55

Authors

Prota, A.E.,Bargsten, K.,Northcote, P.T.,Marsh, M.,Altmann, K.H.,Miller, J.H.,Diaz, J.F.,Steinmetz, M.O. (deposition date: 2013-12-18, release date: 2014-03-12, Last modification date: 2023-09-20)

Primary citation

Prota, A.E.,Bargsten, K.,Northcote, P.T.,Marsh, M.,Altmann, K.H.,Miller, J.H.,Diaz, J.F.,Steinmetz, M.O.
Structural basis of microtubule stabilization by laulimalide and peloruside a.
Angew.Chem.Int.Ed.Engl., 53:1621-1625, 2014

PubMed 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 β-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 β-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.

PubMed: 24470331
DOI: 10.1002/anie.201307749

Experimental method

X-RAY DIFFRACTION (2.4 Å)