5LOV

DZ-2384 tubulin complex

Summary for 5LOV

• Entry DOI: 10.2210/pdb5lov/pdb
• Related: 4I55 5J2T
• Descriptor: Tubulin alpha-1B chain, DZ 2384, PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER, ... (12 entities in total)
• Functional Keywords: cell cycle, tubulin fold, cytoskeleton, microtubule
• Biological source: Rattus norvegicus (Norway Rat); More
• Cellular location: Cytoplasm, cytoskeleton: P81947 Q6B856; Golgi apparatus : P63043
• Total number of polymer chains: 6
• Total formula weight: 265023.20

Authors

Prota, A.E.,Steinmetz, M.O.,Shore, G.C.,Brouhard, G.,Roulston, A. (deposition date: 2016-08-10, release date: 2016-11-30, Last modification date: 2024-01-10)

Primary citation

Wieczorek, M.,Tcherkezian, J.,Bernier, C.,Prota, A.E.,Chaaban, S.,Rolland, Y.,Godbout, C.,Hancock, M.A.,Arezzo, J.C.,Ocal, O.,Rocha, C.,Olieric, N.,Hall, A.,Ding, H.,Bramoulle, A.,Annis, M.G.,Zogopoulos, G.,Harran, P.G.,Wilkie, T.M.,Brekken, R.A.,Siegel, P.M.,Steinmetz, M.O.,Shore, G.C.,Brouhard, G.J.,Roulston, A.
The synthetic diazonamide DZ-2384 has distinct effects on microtubule curvature and dynamics without neurotoxicity.
Sci Transl Med, 8:365ra159-365ra159, 2016

PubMed Abstract: Microtubule-targeting agents (MTAs) are widely used anticancer agents, but toxicities such as neuropathy limit their clinical use. MTAs bind to and alter the stability of microtubules, causing cell death in mitosis. We describe DZ-2384, a preclinical compound that exhibits potent antitumor activity in models of multiple cancer types. It has an unusually high safety margin and lacks neurotoxicity in rats at effective plasma concentrations. DZ-2384 binds the vinca domain of tubulin in a distinct way, imparting structurally and functionally different effects on microtubule dynamics compared to other vinca-binding compounds. X-ray crystallography and electron microscopy studies demonstrate that DZ-2384 causes straightening of curved protofilaments, an effect proposed to favor polymerization of tubulin. Both DZ-2384 and the vinca alkaloid vinorelbine inhibit microtubule growth rate; however, DZ-2384 increases the rescue frequency and preserves the microtubule network in nonmitotic cells and in primary neurons. This differential modulation of tubulin results in a potent MTA therapeutic with enhanced safety.

PubMed: 27856798
DOI: 10.1126/scitranslmed.aag1093

Experimental method

X-RAY DIFFRACTION (2.4 Å)