5MF4

Tubulin-Dictyostatin complex

Summary for 5MF4

• Entry DOI: 10.2210/pdb5mf4/pdb
• Related: 5LXS 5LXT
• Descriptor: Tubulin alpha-1B chain, (3~{Z},5~{E},7~{R},8~{S},10~{S},11~{Z},13~{S},14~{R},15~{S},17~{S},20~{R},21~{S},22~{S})-22-[(2~{S},3~{Z})-hexa-3,5-dien-2-yl]-7,13,15,17,21-pentamethyl-8,10,14,20-tetrakis(oxidanyl)-1-oxacyclodocosa-3,5,11-trien-2-one, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, ... (13 entities in total)
• Functional Keywords: cell cycle, tubulin fold, cytoskeleton, microtubule
• Biological source: Rattus norvegicus (Norway Rat); More
• Total number of polymer chains: 6
• Total formula weight: 265926.91

Authors

Trigili, C.,Barasoain, I.,Sanchez-Murcia, P.A.,Bargsten, K.,Redondo-Horcajo, M.,Nogales, A.,Gardner, N.M.,Meyer, A.,Naylor, G.J.,Gomez-Rubio, E.,Gago, F.,Steinmetz, M.O.,Paterson, I.,Prota, A.E.,Diaz, J.F. (deposition date: 2016-11-17, release date: 2017-09-20, Last modification date: 2024-01-17)

Primary citation

Trigili, C.,Barasoain, I.,Sanchez-Murcia, P.A.,Bargsten, K.,Redondo-Horcajo, M.,Nogales, A.,Gardner, N.M.,Meyer, A.,Naylor, G.J.,Gomez-Rubio, E.,Gago, F.,Steinmetz, M.O.,Paterson, I.,Prota, A.E.,Diaz, J.F.
Structural Determinants of the Dictyostatin Chemotype for Tubulin Binding Affinity and Antitumor Activity Against Taxane- and Epothilone-Resistant Cancer Cells.
ACS Omega, 1:1192-1204, 2016

PubMed Abstract: A combined biochemical, structural, and cell biology characterization of dictyostatin is described, which enables an improved understanding of the structural determinants responsible for the high-affinity binding of this anticancer agent to the taxane site in microtubules (MTs). The study reveals that this macrolide is highly optimized for MT binding and that only a few of the structural modifications featured in a library of synthetic analogues resulted in small gains in binding affinity. The high efficiency of the dictyostatin chemotype in overcoming various kinds of clinically relevant resistance mechanisms highlights its potential for therapeutic development for the treatment of drug-resistant tumors. A structural explanation is advanced to account for the synergy observed between dictyostatin and taxanes on the basis of their differential effects on the MT lattice. The X-ray crystal structure of a tubulin-dictyostatin complex and additional molecular modeling have allowed the rationalization of the structure-activity relationships for a set of synthetic dictyostatin analogues, including the highly active hybrid with discodermolide. Altogether, the work reported here is anticipated to facilitate the improved design and synthesis of more efficacious dictyostatin analogues and hybrids with other MT-stabilizing agents.

PubMed: 30023505
DOI: 10.1021/acsomega.6b00317

Experimental method

X-RAY DIFFRACTION (2.3 Å)