5yj8
From Proteopedia
(Difference between revisions)
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<StructureSection load='5yj8' size='340' side='right' caption='[[5yj8]], [[Resolution|resolution]] 1.76Å' scene=''> | <StructureSection load='5yj8' size='340' side='right' caption='[[5yj8]], [[Resolution|resolution]] 1.76Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>[[5yj8]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5YJ8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5YJ8 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5yj8]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5YJ8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5YJ8 FirstGlance]. <br> |
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8W9:5-(aminomethyl)-1,3-dimethyl-benzimidazol-2-one'>8W9</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8W9:5-(aminomethyl)-1,3-dimethyl-benzimidazol-2-one'>8W9</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | ||
| + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TDRD3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=5yj8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5yj8 OCA], [http://pdbe.org/5yj8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5yj8 RCSB], [http://www.ebi.ac.uk/pdbsum/5yj8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5yj8 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=5yj8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5yj8 OCA], [http://pdbe.org/5yj8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5yj8 RCSB], [http://www.ebi.ac.uk/pdbsum/5yj8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5yj8 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[[http://www.uniprot.org/uniprot/TDRD3_HUMAN TDRD3_HUMAN]] Scaffolding protein that specifically recognizes and binds dimethylarginine-containing proteins. In nucleus, acts as a coactivator: recognizes and binds asymmetric dimethylation on the core histone tails associated with transcriptional activation (H3R17me2a and H4R3me2a) and recruits proteins at these arginine-methylated loci. In cytoplasm, may play a role in the assembly and/or disassembly of mRNA stress granules and in the regulation of translation of target mRNAs by binding Arg/Gly-rich motifs (GAR) in dimethylarginine-containing proteins.<ref>PMID:18632687</ref> <ref>PMID:15955813</ref> <ref>PMID:21172665</ref> | [[http://www.uniprot.org/uniprot/TDRD3_HUMAN TDRD3_HUMAN]] Scaffolding protein that specifically recognizes and binds dimethylarginine-containing proteins. In nucleus, acts as a coactivator: recognizes and binds asymmetric dimethylation on the core histone tails associated with transcriptional activation (H3R17me2a and H4R3me2a) and recruits proteins at these arginine-methylated loci. In cytoplasm, may play a role in the assembly and/or disassembly of mRNA stress granules and in the regulation of translation of target mRNAs by binding Arg/Gly-rich motifs (GAR) in dimethylarginine-containing proteins.<ref>PMID:18632687</ref> <ref>PMID:15955813</ref> <ref>PMID:21172665</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | As a reader of di-methylated arginine on various proteins, such as histone, RNA polymerase II, PIWI and Fragile X mental retardation protein, the Tudor domain of Tudor domain-containing protein 3 (TDRD3) mediates transcriptional activation in nucleus and formation of stress granules in the cytoplasm. Despite the TDRD3 implication in cancer cell proliferation and invasion, warheads to block the di-methylated arginine recognition pocket of the TDRD3 Tudor domain have not yet been uncovered. Here we identified 14 small molecule hits against the TDRD3 Tudor domain through NMR fragment-based screening. These hits were further cross-validated by using competitive fluorescence polarization and isothermal titration calorimetry experiments. The crystal structure of the TDRD3 Tudor domain in complex with hit 1 reveals a distinct binding mode from the nature substrate. Hit 1 protrudes into the aromatic cage of the TDRD3 Tudor domain, where the aromatic residues are tilted to accommodate a sandwich-like pi-pi interaction. The side chain of the conserved residue N596 swings away 3.1 A to form a direct hydrogen bond with hit 1. Moreover, this compound shows a decreased affinity against the single Tudor domain of survival motor neuron protein, but no detectable binding to neither the tandem Tudor domain of TP53-binding protein 1 nor the extended Tudor domain of staphylococcal nuclease domain-containing protein 1. Our work depicts the structural plasticity of the TDRD3 Tudor domain and paves the way for the subsequent structure-guided discovery of selective inhibitors targeting Tudor domains. DATABASE: Structural data are available in the PDB under the accession number 5YJ8. | ||
| + | |||
| + | Structural plasticity of the TDRD3 Tudor domain probed by a fragment screening hit.,Liu J, Zhang S, Liu M, Liu Y, Nshogoza G, Gao J, Ma R, Yang Y, Wu J, Zhang J, Li F, Ruan K FEBS J. 2018 Apr 12. doi: 10.1111/febs.14469. PMID:29645362<ref>PMID:29645362</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 5yj8" style="background-color:#fffaf0;"></div> | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Human]] | ||
[[Category: Liu, J]] | [[Category: Liu, J]] | ||
[[Category: Ruan, K]] | [[Category: Ruan, K]] | ||
Revision as of 05:54, 16 May 2018
Identification of a small molecule inhibitor for the Tudor domain of TDRD3
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