6ls4: Difference between revisions
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==== | ==A novel anti-tumor agent S-40 in complex with tubulin== | ||
<StructureSection load='6ls4' size='340' side='right'caption='[[6ls4]]' scene=''> | <StructureSection load='6ls4' size='340' side='right'caption='[[6ls4]], [[Resolution|resolution]] 2.40Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br> | <table><tr><td colspan='2'>[[6ls4]] is a 5 chain structure with sequence from [https://en.wikipedia.org/wiki/Sus_scrofa Sus scrofa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6LS4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6LS4 FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6ls4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ls4 OCA], [https://pdbe.org/6ls4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ls4 RCSB], [https://www.ebi.ac.uk/pdbsum/6ls4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ls4 ProSAT]</span></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.4Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=GTP:GUANOSINE-5-TRIPHOSPHATE'>GTP</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=S40:3-[(4-cyclopropylphenyl)sulfonylamino]-4-methyl-N-(pyridin-3-ylmethyl)benzamide'>S40</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6ls4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ls4 OCA], [https://pdbe.org/6ls4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ls4 RCSB], [https://www.ebi.ac.uk/pdbsum/6ls4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ls4 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/TBA1B_PIG TBA1B_PIG] 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. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The tubulin colchicine binding site has been recognized as an attractive drug target to combat cancer, but none of the candidate drugs have been approved for medical treatment. We recently identified a structurally distinct small molecule S-40 as an oral potent tubulin destabilizing agent. Crystal structure analysis of S-40 in a complex with tubulin at a resolution of 2.4 A indicated that S-40 occupies all 3 zones in the colchicine pocket with interactions different from known microtubule inhibitors, presenting unique effects on assembly and curvature of tubulin dimers. S-40 overcomes paclitaxel resistance and lacks neurotoxicity, which are the main obstacles limiting clinical applications of paclitaxel. Moreover, S-40 harbors the ability to inhibit growth of cancer cell lines as well as patient-derived organoids, induce mitotic arrest and cell apoptosis. Xenograft mouse models of human prostate cancer DU145, non-small cell lung cancer NCI-H1299 and paclitaxel-resistant A549 were strongly restrained without apparent side effects by S-40 oral administration once daily. These findings provide evidence for the development of S-40 as the next generation of orally effective microtubule inhibitors for cancer therapy. | |||
A novel orally active microtubule destabilizing agent S-40 targets the colchicine-binding site and shows potent antitumor activity.,Du T, Lin S, Ji M, Xue N, Liu Y, Zhang Z, Zhang K, Zhang J, Zhang Y, Wang Q, Sheng L, Li Y, Lu D, Chen X, Xu H Cancer Lett. 2020 Dec 28;495:22-32. doi: 10.1016/j.canlet.2020.08.040. Epub 2020 , Sep 12. PMID:32931884<ref>PMID:32931884</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6ls4" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: | [[Category: Sus scrofa]] | ||
[[Category: Chen X]] | |||
[[Category: Du T]] | |||
[[Category: Ji M]] | |||
[[Category: Lin S]] | |||
[[Category: Liu Y]] | |||
[[Category: Lu D]] | |||
[[Category: Xu H]] | |||
[[Category: Xue N]] | |||
[[Category: Zhang K]] | |||
Latest revision as of 17:48, 29 November 2023
A novel anti-tumor agent S-40 in complex with tubulinA novel anti-tumor agent S-40 in complex with tubulin
Structural highlights
FunctionTBA1B_PIG 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. Publication Abstract from PubMedThe tubulin colchicine binding site has been recognized as an attractive drug target to combat cancer, but none of the candidate drugs have been approved for medical treatment. We recently identified a structurally distinct small molecule S-40 as an oral potent tubulin destabilizing agent. Crystal structure analysis of S-40 in a complex with tubulin at a resolution of 2.4 A indicated that S-40 occupies all 3 zones in the colchicine pocket with interactions different from known microtubule inhibitors, presenting unique effects on assembly and curvature of tubulin dimers. S-40 overcomes paclitaxel resistance and lacks neurotoxicity, which are the main obstacles limiting clinical applications of paclitaxel. Moreover, S-40 harbors the ability to inhibit growth of cancer cell lines as well as patient-derived organoids, induce mitotic arrest and cell apoptosis. Xenograft mouse models of human prostate cancer DU145, non-small cell lung cancer NCI-H1299 and paclitaxel-resistant A549 were strongly restrained without apparent side effects by S-40 oral administration once daily. These findings provide evidence for the development of S-40 as the next generation of orally effective microtubule inhibitors for cancer therapy. A novel orally active microtubule destabilizing agent S-40 targets the colchicine-binding site and shows potent antitumor activity.,Du T, Lin S, Ji M, Xue N, Liu Y, Zhang Z, Zhang K, Zhang J, Zhang Y, Wang Q, Sheng L, Li Y, Lu D, Chen X, Xu H Cancer Lett. 2020 Dec 28;495:22-32. doi: 10.1016/j.canlet.2020.08.040. Epub 2020 , Sep 12. PMID:32931884[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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