6br1: Difference between revisions
No edit summary |
No edit summary |
||
| Line 3: | Line 3: | ||
<StructureSection load='6br1' size='340' side='right' caption='[[6br1]], [[Resolution|resolution]] 2.30Å' scene=''> | <StructureSection load='6br1' size='340' side='right' caption='[[6br1]], [[Resolution|resolution]] 2.30Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6br1]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/ ] 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=6BR1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BR1 FirstGlance]. <br> | <table><tr><td colspan='2'>[[6br1]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Chick Chick], [http://en.wikipedia.org/wiki/Human Human] 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=6BR1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BR1 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=E3Y:2-chloro-4-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)pyrido[2,3-d]pyrimidine'>E3Y</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='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=E3Y:2-chloro-4-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)pyrido[2,3-d]pyrimidine'>E3Y</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=9606 HUMAN]), 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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6br1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6br1 OCA], [http://pdbe.org/6br1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6br1 RCSB], [http://www.ebi.ac.uk/pdbsum/6br1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6br1 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=6br1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6br1 OCA], [http://pdbe.org/6br1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6br1 RCSB], [http://www.ebi.ac.uk/pdbsum/6br1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6br1 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| Line 18: | Line 19: | ||
</div> | </div> | ||
<div class="pdbe-citations 6br1" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 6br1" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Stathmin|Stathmin]] | |||
*[[Tubulin|Tubulin]] | |||
*[[Tubulin tyrosine ligase|Tubulin tyrosine ligase]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Chick]] | |||
[[Category: Human]] | |||
[[Category: Sus scrofa]] | [[Category: Sus scrofa]] | ||
[[Category: Kumar, G]] | [[Category: Kumar, G]] | ||
Revision as of 10:56, 21 February 2019
Tubulin-RB3_SLD-TTL in complex with heterocyclic pyrimidine compound 4aTubulin-RB3_SLD-TTL in complex with heterocyclic pyrimidine compound 4a
Structural highlights
Function[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. [STMN4_HUMAN] Exhibits microtubule-destabilizing activity. [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] Publication Abstract from PubMedWe 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||