5sb5: Difference between revisions
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==Tubulin-todalam-9-complex== | ==Tubulin-todalam-9-complex== | ||
<StructureSection load='5sb5' size='340' side='right'caption='[[5sb5]]' scene=''> | <StructureSection load='5sb5' size='340' side='right'caption='[[5sb5]], [[Resolution|resolution]] 2.31Å' 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=5SB5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5SB5 FirstGlance]. <br> | <table><tr><td colspan='2'>[[5sb5]] 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=5SB5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5SB5 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=5sb5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5sb5 OCA], [https://pdbe.org/5sb5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5sb5 RCSB], [https://www.ebi.ac.uk/pdbsum/5sb5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5sb5 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]] 2.31Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4CJ:N-{4-[2-(3-fluoroanilino)-1,3-thiazol-4-yl]phenyl}acetamide'>4CJ</scene>, <scene name='pdbligand=ACP:PHOSPHOMETHYLPHOSPHONIC+ACID+ADENYLATE+ESTER'>ACP</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</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=5sb5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5sb5 OCA], [https://pdbe.org/5sb5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5sb5 RCSB], [https://www.ebi.ac.uk/pdbsum/5sb5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5sb5 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[https://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. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
In this study, we capitalized on our previously performed crystallographic fragment screen and developed the antitubulin small molecule Todalam with only two rounds of straightforward chemical synthesis. Todalam binds to a novel tubulin site, disrupts microtubule networks in cells, arrests cells in G2/M, induces cell death, and synergizes with vinblastine. The compound destabilizes microtubules by acting as a molecular plug that sterically inhibits the curved-to-straight conformational switch in the alpha-tubulin subunit, and by sequestering tubulin dimers into assembly incompetent oligomers. Our results describe for the first time the generation of a fully rationally designed small molecule tubulin inhibitor from a fragment, which displays a unique molecular mechanism of action. They thus demonstrate the usefulness of tubulin-binding fragments as valuable starting points for innovative antitubulin drug and chemical probe discovery campaigns. | |||
Rational Design of a Novel Tubulin Inhibitor with a Unique Mechanism of Action.,Muhlethaler T, Milanos L, Ortega JA, Blum TB, Gioia D, Roy B, Prota AE, Cavalli A, Steinmetz MO Angew Chem Int Ed Engl. 2022 Jun 20;61(25):e202204052. doi: , 10.1002/anie.202204052. Epub 2022 Apr 25. PMID:35404502<ref>PMID:35404502</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 5sb5" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Stathmin-4 3D structures|Stathmin-4 3D structures]] | |||
*[[Tubulin 3D Structures|Tubulin 3D Structures]] | |||
*[[Tubulin tyrosine ligase 3D structures|Tubulin tyrosine ligase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Bos taurus]] | |||
[[Category: Gallus gallus]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Rattus norvegicus]] | |||
[[Category: Blum TB]] | [[Category: Blum TB]] | ||
[[Category: Cavalli A]] | [[Category: Cavalli A]] | ||
Latest revision as of 12:59, 22 May 2024
Tubulin-todalam-9-complexTubulin-todalam-9-complex
Structural highlights
FunctionTBA1B_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. Publication Abstract from PubMedIn this study, we capitalized on our previously performed crystallographic fragment screen and developed the antitubulin small molecule Todalam with only two rounds of straightforward chemical synthesis. Todalam binds to a novel tubulin site, disrupts microtubule networks in cells, arrests cells in G2/M, induces cell death, and synergizes with vinblastine. The compound destabilizes microtubules by acting as a molecular plug that sterically inhibits the curved-to-straight conformational switch in the alpha-tubulin subunit, and by sequestering tubulin dimers into assembly incompetent oligomers. Our results describe for the first time the generation of a fully rationally designed small molecule tubulin inhibitor from a fragment, which displays a unique molecular mechanism of action. They thus demonstrate the usefulness of tubulin-binding fragments as valuable starting points for innovative antitubulin drug and chemical probe discovery campaigns. Rational Design of a Novel Tubulin Inhibitor with a Unique Mechanism of Action.,Muhlethaler T, Milanos L, Ortega JA, Blum TB, Gioia D, Roy B, Prota AE, Cavalli A, Steinmetz MO Angew Chem Int Ed Engl. 2022 Jun 20;61(25):e202204052. doi: , 10.1002/anie.202204052. Epub 2022 Apr 25. PMID:35404502[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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