7ce8: Difference between revisions
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==== | ==Crystal structure of T2R-TTL-Compound11 complex== | ||
<StructureSection load='7ce8' size='340' side='right'caption='[[7ce8]]' scene=''> | <StructureSection load='7ce8' size='340' side='right'caption='[[7ce8]], [[Resolution|resolution]] 2.73Å' 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'>[[7ce8]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Gallus_gallus Gallus gallus], [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus] and [https://en.wikipedia.org/wiki/Sus_scrofa Sus scrofa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7CE8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7CE8 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=7ce8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ce8 OCA], [https://pdbe.org/7ce8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ce8 RCSB], [https://www.ebi.ac.uk/pdbsum/7ce8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ce8 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]] 2.725Å</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=AEX:N-butyl-9H-beta-carbolin-3-amine'>AEX</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <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></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=7ce8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ce8 OCA], [https://pdbe.org/7ce8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ce8 RCSB], [https://www.ebi.ac.uk/pdbsum/7ce8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ce8 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 == | |||
Here, we report a novel mechanism to selectively degrade target proteins. 3-(3-Phenoxybenzyl)amino-beta-carboline (PAC), a tubulin inhibitor, promotes selective degradation of alphabeta-tubulin heterodimers. Biochemical studies have revealed that PAC specifically denatures tubulin, making it prone to aggregation that predisposes it to ubiquitinylation and then degradation. The degradation is mediated by a single hydrogen bond formed between the pyridine nitrogen of PAC and betaGlu198, which is identified as a low-barrier hydrogen bond (LBHB). In contrast, another two tubulin inhibitors that only form normal hydrogen bonds with betaGlu198 exhibit no degradation effect. Thus, the LBHB accounts for the degradation. We then screened for compounds capable of forming an LBHB with betaGlu198 and demonstrated that BML284, a Wnt signaling activator, also promotes tubulin heterodimer degradation through the LBHB. Our study provided a unique example of LBHB function and identified a novel approach to obtain tubulin degraders. | |||
Small Molecules Promote Selective Denaturation and Degradation of Tubulin Heterodimers through a Low-Barrier Hydrogen Bond.,Yang J, Li Y, Qiu Q, Wang R, Yan W, Yu Y, Niu L, Pei H, Wei H, Ouyang L, Ye H, Xu D, Wei Y, Chen Q, Chen L J Med Chem. 2022 Jul 14;65(13):9159-9173. doi: 10.1021/acs.jmedchem.2c00379. Epub, 2022 Jun 28. PMID:35762925<ref>PMID:35762925</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7ce8" 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__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Gallus gallus]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: | [[Category: Rattus norvegicus]] | ||
[[Category: Sus scrofa]] | |||
[[Category: Chen LJ]] | |||
[[Category: Chen Q]] | |||
[[Category: Yang JH]] | |||
[[Category: Yu Y]] | |||
Latest revision as of 19:06, 29 November 2023
Crystal structure of T2R-TTL-Compound11 complexCrystal structure of T2R-TTL-Compound11 complex
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 PubMedHere, we report a novel mechanism to selectively degrade target proteins. 3-(3-Phenoxybenzyl)amino-beta-carboline (PAC), a tubulin inhibitor, promotes selective degradation of alphabeta-tubulin heterodimers. Biochemical studies have revealed that PAC specifically denatures tubulin, making it prone to aggregation that predisposes it to ubiquitinylation and then degradation. The degradation is mediated by a single hydrogen bond formed between the pyridine nitrogen of PAC and betaGlu198, which is identified as a low-barrier hydrogen bond (LBHB). In contrast, another two tubulin inhibitors that only form normal hydrogen bonds with betaGlu198 exhibit no degradation effect. Thus, the LBHB accounts for the degradation. We then screened for compounds capable of forming an LBHB with betaGlu198 and demonstrated that BML284, a Wnt signaling activator, also promotes tubulin heterodimer degradation through the LBHB. Our study provided a unique example of LBHB function and identified a novel approach to obtain tubulin degraders. Small Molecules Promote Selective Denaturation and Degradation of Tubulin Heterodimers through a Low-Barrier Hydrogen Bond.,Yang J, Li Y, Qiu Q, Wang R, Yan W, Yu Y, Niu L, Pei H, Wei H, Ouyang L, Ye H, Xu D, Wei Y, Chen Q, Chen L J Med Chem. 2022 Jul 14;65(13):9159-9173. doi: 10.1021/acs.jmedchem.2c00379. Epub, 2022 Jun 28. PMID:35762925[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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