5JH7

Tubulin-Eribulin complex

Summary for 5JH7

• Entry DOI: 10.2210/pdb5jh7/pdb
• Descriptor: Tubulin alpha-1B chain, GUANOSINE-5'-DIPHOSPHATE, (1S,3S,6S,9S,12S,14R,16R,18S,20R,21R,22S,26R,29S,31R,32S,33R,35R,36S)-20-[(2S)-3-amino-2-hydroxypropyl]-21-methoxy-14-methyl-8,15-dimethylidene-2,19,30,34,37,39,40,41-octaoxanonacyclo[24.9.2.1~3,32~.1~3,33~.1~6,9~.1~12,16~.0~18,22~.0~29,36~.0~31,35~]hentetracontan-24-one (non-preferred name), ... (15 entities in total)
• Functional Keywords: cell cycle, cytoskeleton, tubulin fold, microtubule
• Biological source: Rattus norvegicus (Rat); More
• Cellular location: Cytoplasm, cytoskeleton: P81947 Q6B856; Golgi apparatus : P63043
• Total number of polymer chains: 6
• Total formula weight: 266158.83

Authors

Doodhi, H.,Prota, A.E.,Rodriguez-Garcia, R.,Xiao, H.,Custar, D.W.,Bargsten, K.,Katrukha, E.A.,Hilbert, M.,Hua, S.,Jiang, K.,Grigoriev, I.,Yang, C.-P.H.,Cox, D.,Band Horwitz, S.,Kapitein, L.C.,Akhmanova, A.,Steinmetz, M.O. (deposition date: 2016-04-20, release date: 2016-06-29, Last modification date: 2024-01-10)

Primary citation

Doodhi, H.,Prota, A.E.,Rodriguez-Garcia, R.,Xiao, H.,Custar, D.W.,Bargsten, K.,Katrukha, E.A.,Hilbert, M.,Hua, S.,Jiang, K.,Grigoriev, I.,Yang, C.P.,Cox, D.,Horwitz, S.B.,Kapitein, L.C.,Akhmanova, A.,Steinmetz, M.O.
Termination of Protofilament Elongation by Eribulin Induces Lattice Defects that Promote Microtubule Catastrophes.
Curr.Biol., 26:1713-1721, 2016

PubMed Abstract: Microtubules are dynamic polymers built of tubulin dimers that attach in a head-to-tail fashion to form protofilaments, which further associate laterally to form a tube. Asynchronous elongation of individual protofilaments can potentially lead to an altered microtubule-end structure that promotes sudden depolymerization, termed catastrophe [1-4]. However, how the dynamics of individual protofilaments relates to overall growth persistence has remained unclear. Here, we used the microtubule targeting anti-cancer drug Eribulin [5-7] to explore the consequences of stalled protofilament elongation on microtubule growth. Using X-ray crystallography, we first revealed that Eribulin binds to a site on β-tubulin that is required for protofilament plus-end elongation. Based on the structural information, we engineered a fluorescent Eribulin molecule. We demonstrate that single Eribulin molecules specifically interact with microtubule plus ends and are sufficient to either trigger a catastrophe or induce slow and erratic microtubule growth in the presence of EB3. Interestingly, we found that Eribulin increases the frequency of EB3 comet "splitting," transient events where a slow and erratically progressing comet is followed by a faster comet. This observation possibly reflects the "healing" of a microtubule lattice. Because EB3 comet splitting was also observed in control microtubules in the absence of any drugs, we propose that Eribulin amplifies a natural pathway toward catastrophe by promoting the arrest of protofilament elongation.

PubMed: 27321995
DOI: 10.1016/j.cub.2016.04.053

Experimental method

X-RAY DIFFRACTION (2.25 Å)