6bs2: Difference between revisions

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<StructureSection load='6bs2' size='340' side='right'caption='[[6bs2]], [[Resolution|resolution]] 2.65&Aring;' scene=''>
<StructureSection load='6bs2' size='340' side='right'caption='[[6bs2]], [[Resolution|resolution]] 2.65&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[6bs2]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Buffalo_rat Buffalo rat], [http://en.wikipedia.org/wiki/Chick Chick] and [http://en.wikipedia.org/wiki/Sus_scrofa Sus scrofa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BS2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BS2 FirstGlance]. <br>
<table><tr><td colspan='2'>[[6bs2]] 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=6BS2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6BS2 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=E9Y:1-(3,6-dimethyl[1,2]oxazolo[5,4-d]pyrimidin-4-yl)-6-methoxy-1,2,3,4-tetrahydroquinoline'>E9Y</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]] 2.65&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6br1|6br1]], [[6brf|6brf]], [[6bry|6bry]]</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=E9Y:1-(3,6-dimethyl[1,2]oxazolo[5,4-d]pyrimidin-4-yl)-6-methoxy-1,2,3,4-tetrahydroquinoline'>E9Y</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='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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6bs2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bs2 OCA], [https://pdbe.org/6bs2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6bs2 RCSB], [https://www.ebi.ac.uk/pdbsum/6bs2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6bs2 ProSAT]</span></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=6bs2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bs2 OCA], [http://pdbe.org/6bs2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6bs2 RCSB], [http://www.ebi.ac.uk/pdbsum/6bs2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6bs2 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[http://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. [[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/A0A287AGU7_PIG A0A287AGU7_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.[RuleBase:RU000352][SAAS:SAAS00031082]
[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 ==
We report the design, synthesis, and biological evaluation of heterocyclic-fused pyrimidines as tubulin polymerization inhibitors targeting the colchicine binding site with significantly improved therapeutic index. Additionally, for the first time, we report high-resolution X-ray crystal structures for the best compounds in this scaffold, 4a, 4b, 6a, and 8b. These structures not only confirm their direct binding to the colchicine site in tubulin and reveal their detailed molecular interactions but also contrast the previously published proposed binding mode. Compounds 4a and 6a significantly inhibited tumor growth in an A375 melanoma xenograft model and were accompanied by elevated levels of apoptosis and disruption of tumor vasculature. Finally, we demonstrated that compound 4a significantly overcame clinically relevant multidrug resistance in a paclitaxel resistant PC-3/TxR prostate cancer xenograft model. Collectively, these studies provide preclinical and structural proof of concept to support the continued development of this scaffold as a new generation of tubulin inhibitors.
 
Heterocyclic-Fused Pyrimidines as Novel Tubulin Polymerization Inhibitors Targeting the Colchicine Binding Site: Structural Basis and Antitumor Efficacy.,Banerjee S, Arnst KE, Wang Y, Kumar G, Deng S, Yang L, Li GB, Yang J, White SW, Li W, Miller DD J Med Chem. 2018 Feb 22;61(4):1704-1718. doi: 10.1021/acs.jmedchem.7b01858. Epub , 2018 Feb 12. PMID:29406710<ref>PMID:29406710</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6bs2" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
*[[Stathmin|Stathmin]]
*[[Stathmin-4 3D structures|Stathmin-4 3D structures]]
*[[Tubulin|Tubulin]]
*[[Tubulin 3D Structures|Tubulin 3D Structures]]
*[[Tubulin tyrosine ligase|Tubulin tyrosine ligase]]
*[[Tubulin tyrosine ligase 3D structures|Tubulin tyrosine ligase 3D structures]]
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Buffalo rat]]
[[Category: Gallus gallus]]
[[Category: Chick]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Rattus norvegicus]]
[[Category: Sus scrofa]]
[[Category: Sus scrofa]]
[[Category: Kumar, G]]
[[Category: Kumar G]]
[[Category: Li, W]]
[[Category: Li W]]
[[Category: Wang, Y]]
[[Category: Wang Y]]
[[Category: White, S W]]
[[Category: White SW]]
[[Category: Cell cycle]]
[[Category: Colchicine cancer]]
[[Category: Microtubule inhibitor]]

Latest revision as of 14:24, 13 March 2024

Tubulin-RB3_SLD-TTL in complex with heterocyclic pyrimidine compound 8b

6bs2, resolution 2.65Å

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