6fii

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Tubulin-Spongistatin complex

Structural highlights

6fii is a 6 chain structure with sequence from Bos taurus, Buffalo rat and Chick. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:ACP, CA, DMS, GDP, GOL, GTP, MES, MG, SG9
Gene:Stmn4 (Buffalo rat), TTL (CHICK)
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[TBA1B_BOVIN] Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain. [STMN4_RAT] Exhibits microtubule-destabilizing activity.[1] [2] [3] [TBB2B_BOVIN] Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain (By similarity).

Publication Abstract from PubMed

Microtubule-targeting agents (MTAs) like taxol and vinblastine are among the most successful chemotherapeutic drugs against cancer. Here, we describe a fluorescence anisotropy-based assay that specifically probes for ligands targeting the recently discovered maytansine site of tubulin. Using this assay, we have determined the dissociation constants of known maytansine site ligands, including the pharmacologically active degradation product of the clinical antibody-drug conjugate trastuzumab emtansine. In addition, we discovered that the two natural products spongistatin-1 and disorazole Z with established cellular potency bind to the maytansine site on beta-tubulin. The high-resolution crystal structures of spongistatin-1 and disorazole Z in complex with tubulin allowed the definition of an additional sub-site adjacent to the pocket shared by all maytansine-site ligands, which could be exploitable as a distinct, separate target site for small molecules. Our study provides a basis for the discovery and development of next-generation MTAs for the treatment of cancer.

A fluorescence anisotropy assay to discover and characterize ligands targeting the maytansine site of tubulin.,Menchon G, Prota AE, Lucena-Agell D, Bucher P, Jansen R, Irschik H, Muller R, Paterson I, Diaz JF, Altmann KH, Steinmetz MO Nat Commun. 2018 May 29;9(1):2106. doi: 10.1038/s41467-018-04535-8. PMID:29844393[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
2 reviews cite this structure
Targeting and extending the eukaryotic druggable genome with natural products: cytoskeletal targets of natural products.
Risinger et al. (2020)
1 more
12 other articles
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See Also

References

  1. ↑ Nakao C, Itoh TJ, Hotani H, Mori N. Modulation of the stathmin-like microtubule destabilizing activity of RB3, a neuron-specific member of the SCG10 family, by its N-terminal domain. J Biol Chem. 2004 May 28;279(22):23014-21. Epub 2004 Mar 22. PMID:15039434 doi:http://dx.doi.org/10.1074/jbc.M313693200
  2. ↑ Gavet O, El Messari S, Ozon S, Sobel A. Regulation and subcellular localization of the microtubule-destabilizing stathmin family phosphoproteins in cortical neurons. J Neurosci Res. 2002 Jun 1;68(5):535-50. PMID:12111843 doi:http://dx.doi.org/10.1002/jnr.10234
  3. ↑ Ravelli RB, Gigant B, Curmi PA, Jourdain I, Lachkar S, Sobel A, Knossow M. Insight into tubulin regulation from a complex with colchicine and a stathmin-like domain. Nature. 2004 Mar 11;428(6979):198-202. PMID:15014504 doi:http://dx.doi.org/10.1038/nature02393
  4. ↑ Menchon G, Prota AE, Lucena-Agell D, Bucher P, Jansen R, Irschik H, Muller R, Paterson I, Diaz JF, Altmann KH, Steinmetz MO. A fluorescence anisotropy assay to discover and characterize ligands targeting the maytansine site of tubulin. Nat Commun. 2018 May 29;9(1):2106. doi: 10.1038/s41467-018-04535-8. PMID:29844393 doi:http://dx.doi.org/10.1038/s41467-018-04535-8

Contents


6fii, resolution 2.41Å

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