|
|
Line 3: |
Line 3: |
| <StructureSection load='6knz' size='340' side='right'caption='[[6knz]], [[Resolution|resolution]] 2.48Å' scene=''> | | <StructureSection load='6knz' size='340' side='right'caption='[[6knz]], [[Resolution|resolution]] 2.48Å' scene=''> |
| == Structural highlights == | | == Structural highlights == |
- | <table><tr><td colspan='2'>[[6knz]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus], [http://en.wikipedia.org/wiki/Buffalo_rat Buffalo rat] and [http://en.wikipedia.org/wiki/Chick Chick]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6KNZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6KNZ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6knz]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus], [https://en.wikipedia.org/wiki/Gallus_gallus Gallus gallus] and [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6KNZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6KNZ FirstGlance]. <br> |
- | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACP:PHOSPHOMETHYLPHOSPHONIC+ACID+ADENYLATE+ESTER'>ACP</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=DN0:2-[5-[4-(2-morpholin-4-ylethoxy)phenyl]pyridin-2-yl]-~{N}-(phenylmethyl)ethanamide'>DN0</scene>, <scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</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></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]] 2.475Å</td></tr> |
- | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Stmn4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Buffalo rat]), TTL ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9031 CHICK])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACP:PHOSPHOMETHYLPHOSPHONIC+ACID+ADENYLATE+ESTER'>ACP</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=DN0:2-[5-[4-(2-morpholin-4-ylethoxy)phenyl]pyridin-2-yl]-~{N}-(phenylmethyl)ethanamide'>DN0</scene>, <scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</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></td></tr> |
- | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6knz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6knz OCA], [http://pdbe.org/6knz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6knz RCSB], [http://www.ebi.ac.uk/pdbsum/6knz PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6knz ProSAT]</span></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=6knz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6knz OCA], [https://pdbe.org/6knz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6knz RCSB], [https://www.ebi.ac.uk/pdbsum/6knz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6knz ProSAT]</span></td></tr> |
| </table> | | </table> |
| == Function == | | == Function == |
- | [[http://www.uniprot.org/uniprot/TBA1B_BOVIN 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. [[http://www.uniprot.org/uniprot/STMN4_RAT STMN4_RAT]] Exhibits microtubule-destabilizing activity.<ref>PMID:15039434</ref> <ref>PMID:12111843</ref> <ref>PMID:15014504</ref> [[http://www.uniprot.org/uniprot/TBB2B_BOVIN 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). | + | [https://www.uniprot.org/uniprot/TBB2B_BOVIN 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). |
| <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
Line 19: |
Line 19: |
| </div> | | </div> |
| <div class="pdbe-citations 6knz" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6knz" style="background-color:#fffaf0;"></div> |
| + | |
| + | ==See Also== |
| + | *[[Stathmin-4 3D structures|Stathmin-4 3D structures]] |
| + | *[[Tubulin 3D Structures|Tubulin 3D Structures]] |
| + | *[[Tubulin tyrosine ligase|Tubulin tyrosine ligase]] |
| == References == | | == References == |
| <references/> | | <references/> |
Line 24: |
Line 29: |
| </StructureSection> | | </StructureSection> |
| [[Category: Bos taurus]] | | [[Category: Bos taurus]] |
- | [[Category: Buffalo rat]] | + | [[Category: Gallus gallus]] |
- | [[Category: Chick]]
| + | |
| [[Category: Large Structures]] | | [[Category: Large Structures]] |
- | [[Category: Chen, Q]] | + | [[Category: Rattus norvegicus]] |
- | [[Category: Yu, Y]] | + | [[Category: Chen Q]] |
- | [[Category: Complex]] | + | [[Category: Yu Y]] |
- | [[Category: Inhibitor]]
| + | |
- | [[Category: Structural protein]]
| + | |
- | [[Category: Tubulin]]
| + | |
| Structural highlights
6knz is a 6 chain structure with sequence from Bos taurus, Gallus gallus and Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| Method: | X-ray diffraction, Resolution 2.475Å |
Ligands: | , , , , , , |
Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
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
KXO1 (tirbanibulin or KX2-391) is as a non-ATP-competitive inhibitor of SRC proto-oncogene non-receptor tyrosine kinase (SRC) and is being clinically investigated for the management of various cancers and actinic keratosis. Recently, KXO1 has also been shown to strongly inhibit tubulin. Interestingly, unlike conventional tubulin-targeting drugs, KXO1 has exhibited low toxicity in preclinical and clinical studies, but the reason for this remains elusive, as are the KXO1-binding site and other details of the interaction of KXO1 with tubulin. Here, cell-based experiments revealed that KXO1 induces tubulin depolymerization and G2/M phase cell cycle arrest at low nanomolar concentrations, similar to colchicine, used as a positive control. Results from biochemical experiments, including an N,N-ethylene-bis(iodoacetamide) competition assay, disclosed that KXO1 binds to the colchicine-binding site on beta-tubulin, further confirmed by the crystal structure of the tubulin-KXO1 complex at 2.5 A resolution. A high-quality electron density map of the crystallographic data enabled us to unambiguously determine the position and orientation of KXO1 in the colchicine-binding site, revealing the detailed interactions between KXO1 and tubulin. We also found that KXO1 binds reversibly to purified tubulin, induces a totally reversible cellular effect (G2/M cell cycle arrest), and possesses no cellular toxicity 5 days after drug washout, explaining KXO1's low toxicity. In summary, we show that KXO1 binds to the colchicine-binding site of tubulin and resolved the crystal structure of the tubulin-KXO1 complex. Importantly, KXO1's reversible binding to tubulin explains its clinically low toxicity, an insight that could guide further clinical applications of KXO1.
Reversible binding of the anticancer drug KXO1 (tirbanibulin) to the colchicine-binding site of beta-tubulin explains KXO1's low clinical toxicity.,Niu L, Yang J, Yan W, Yu Y, Zheng Y, Ye H, Chen Q, Chen L J Biol Chem. 2019 Oct 18. pii: RA119.010732. doi: 10.1074/jbc.RA119.010732. PMID:31628188[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Niu L, Yang J, Yan W, Yu Y, Zheng Y, Ye H, Chen Q, Chen L. Reversible binding of the anticancer drug KXO1 (tirbanibulin) to the colchicine-binding site of beta-tubulin explains KXO1's low clinical toxicity. J Biol Chem. 2019 Oct 18. pii: RA119.010732. doi: 10.1074/jbc.RA119.010732. PMID:31628188 doi:http://dx.doi.org/10.1074/jbc.RA119.010732
|