| Structural highlights
5osk 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: | , , , , , , , , |
| 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
Quinazolinone-based anti-cancer agents were designed, decorated with functional groups from a 2-methoxyestradiol-based microtubule disruptor series, incorporating the aryl sulfamate motif of steroid sulfatase (STS) inhibitors. The steroidal AB-ring system was mimicked, favoring conformations with an N-2 substituent occupying D-ring space. Evaluation against breast and prostate tumor cell lines identified 7b with DU-145 anti-proliferative activity (GI50 300 nM). A preliminary structure-activity relationship afforded compounds (e.g. 7j GI50 50 nM) with activity exceeding that of the parent. Both 7b and 7j inhibit tubulin assembly in vitro and colchicine binding and 7j was successfully co-crystallized with the alphabeta-tubulin heterodimer as the first of its class, its sulfamate group interacting positively at the colchicine binding site. Microtubule destabilization by 7j likely prevents the curved-to-straight conformational transition. Quinazolinone sulfamates surprisingly showed weak STS inhibition. Preliminary in vivo studies in a multiple myeloma xenograft model for 7b showed oral activity, confirming the promise of this template.
Quinazolinone-based Anticancer Agents: Synthesis, Anti-proliferative SAR, Anti-tubulin Activity and Tubulin Co-crystal Structure.,Dohle W, Jourdan FL, Menchon G, Prota AE, Foster PA, Mannion P, Hamel E, Thomas MP, Kasprzyk PG, Ferrandis E, Steinmetz MO, Leese MP, Potter BVL J Med Chem. 2017 Dec 11. doi: 10.1021/acs.jmedchem.7b01474. PMID:29227648[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
- ↑ Dohle W, Jourdan FL, Menchon G, Prota AE, Foster PA, Mannion P, Hamel E, Thomas MP, Kasprzyk PG, Ferrandis E, Steinmetz MO, Leese MP, Potter BVL. Quinazolinone-based Anticancer Agents: Synthesis, Anti-proliferative SAR, Anti-tubulin Activity and Tubulin Co-crystal Structure. J Med Chem. 2017 Dec 11. doi: 10.1021/acs.jmedchem.7b01474. PMID:29227648 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b01474
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