View source for 6knz


==Crystal structure of T2R-TTL-KXO1 complex==
<StructureSection load='6knz' size='340' side='right'caption='[[6knz]], [[Resolution|resolution]] 2.48&Aring;' scene=''>
== Structural highlights ==
<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='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.475&#8491;</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'>[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>
== Function ==
[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;">
== 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<ref>PMID:31628188</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</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/>
__TOC__
</StructureSection>
[[Category: Bos taurus]]
[[Category: Gallus gallus]]
[[Category: Large Structures]]
[[Category: Rattus norvegicus]]
[[Category: Chen Q]]
[[Category: Yu Y]]