| Structural highlights
5lp6 is a 6 chain structure with sequence from [1] and Bos taurus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[STMN4_RAT] Exhibits microtubule-destabilizing activity.[1] [2] [3] [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. [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 (MT) dynamic behaviour is an attractive drug target for chemotherapy, whose regulation by MT-stabilizing and destabilizing agents has been fruitfully applied in treating several types of cancers. MT-stabilizing agents are also emerging as potential remedies for neurodegenerative conditions, such as Alzheimer's and Parkinson's disease, although single-target drugs are not expected to fully cure these complex pathologies. Drug combination often displays enhanced efficacy with respect to mono-therapies. In particular, MT-targeting bivalent compounds (MTBCs) represent a promising class of molecules; however, surprisingly, the majority of MTBCs reported so far exhibit equal if not less efficacy than their building monomers. In order to shed light on MTBCs poor performance, we characterised through a set of complementary approaches thiocolchine (TH) and two bivalent TH-homodimers as prototype molecules. First, the binding affinities of these three molecules were assessed, then we obtained the crystallographic structure of a tubulin-TH complex. The binding affinities were interpreted in light of structural data and of molecular dynamics simulations. Finally, their effects on MT cytoskeleton and cell survival were validated on HeLa cells. The ensemble of these data provides chemical and structural considerations on how a successful rational design of MTBCs should be conceived.
Tools for the rational design of bivalent microtubule-targeting drugs.,Marangon J, Christodoulou MS, Casagrande FV, Tiana G, Dalla Via L, Aliverti A, Passarella D, Cappelletti G, Ricagno S Biochem Biophys Res Commun. 2016 Oct 7;479(1):48-53. doi:, 10.1016/j.bbrc.2016.09.022. Epub 2016 Sep 7. PMID:27613098[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ Marangon J, Christodoulou MS, Casagrande FV, Tiana G, Dalla Via L, Aliverti A, Passarella D, Cappelletti G, Ricagno S. Tools for the rational design of bivalent microtubule-targeting drugs. Biochem Biophys Res Commun. 2016 Oct 7;479(1):48-53. doi:, 10.1016/j.bbrc.2016.09.022. Epub 2016 Sep 7. PMID:27613098 doi:http://dx.doi.org/10.1016/j.bbrc.2016.09.022
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