| Structural highlights
5xag is a 6 chain structure with sequence from Bovin, Buffalo rat and Chick. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , , , , , , |
| Related: | 5xaf |
| Gene: | TUBB2B (BOVIN), 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
A diverse of chiral beta-lactam bridged analogues of combretastatin A-4 (CA-4), 3-substituted 1,4-diaryl-2-azetidinones, were asymmetrically synthesized and biologically evaluated, leading to identify a number of potent anti-proliferative compounds represented by 14b and 14c with IC50 values of 0.001-0.021 muM, against four human cancer cell lines (A2780, Hela, SKOV-3 and MDA-MB-231). Structure-activity relationship (SAR) studies on all stereoisomers of 14b and 14c revealed that the absolute configurations of the chiral centers at 3- and 4-position were critically important for the activity and generally a trans configuration between the "A" and "B" rings is optimal. In addition, 14b and 14c displayed less cytotoxicity on normal human oviduct epithelial cells than malignant cells indicating good selectivity in vitro. Further biochemical evaluation and cocrystal structures with tubulin demonstrated that both compounds disrupted tubulin polymerization through interacting at the colchicine-binding site, suppressed angiogenesis in vitro and in vivo, blocked cell cycle progression at mitotic phase and induced cellular apoptosis. The in vivo assays verified that both compounds inhibited xenograft tumor growth in nude mice with acceptable therapeutic window, showing promising potentials for further clinical development.
Design, synthesis, biological evaluation and cocrystal structures with tubulin of chiral beta-lactam bridged combretastatin A-4 analogues as potent antitumor agents.,Zhou P, Liang Y, Zhang H, Jiang H, Feng K, Xu P, Wang J, Wang X, Ding K, Luo C, Liu M, Wang Y Eur J Med Chem. 2017 Dec 7;144:817-842. doi: 10.1016/j.ejmech.2017.12.004. PMID:29306206[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
- ↑ Zhou P, Liang Y, Zhang H, Jiang H, Feng K, Xu P, Wang J, Wang X, Ding K, Luo C, Liu M, Wang Y. Design, synthesis, biological evaluation and cocrystal structures with tubulin of chiral beta-lactam bridged combretastatin A-4 analogues as potent antitumor agents. Eur J Med Chem. 2017 Dec 7;144:817-842. doi: 10.1016/j.ejmech.2017.12.004. PMID:29306206 doi:http://dx.doi.org/10.1016/j.ejmech.2017.12.004
|
