6v9t

From Proteopedia

(Difference between revisions)

Current revision

Tudor domain of TDRD3 in complex with a small molecule

Structural highlights

6v9t is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.154Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.^[1] ^[2] ^[3]

Publication Abstract from PubMed

Survival of motor neuron (SMN) functions in diverse biological pathways via recognition of symmetric dimethylarginine (Rme2s) on proteins by its Tudor domain, and deficiency of SMN leads to spinal muscular atrophy. Here we report a potent and selective antagonist with a 4-iminopyridine scaffold targeting the Tudor domain of SMN. Our structural and mutagenesis studies indicate that both the aromatic ring and imino groups of compound 1 contribute to its selective binding to SMN. Various on-target engagement assays support that compound 1 specifically recognizes SMN in a cellular context and prevents the interaction of SMN with the R1810me2s of RNA polymerase II subunit POLR2A, resulting in transcription termination and R-loop accumulation mimicking SMN depletion. Thus, in addition to the antisense, RNAi and CRISPR/Cas9 techniques, potent SMN antagonists could be used as an efficient tool to understand the biological functions of SMN.

A small molecule antagonist of SMN disrupts the interaction between SMN and RNAP II.,Liu Y, Iqbal A, Li W, Ni Z, Wang Y, Ramprasad J, Abraham KJ, Zhang M, Zhao DY, Qin S, Loppnau P, Jiang H, Guo X, Brown PJ, Zhen X, Xu G, Mekhail K, Ji X, Bedford MT, Greenblatt JF, Min J Nat Commun. 2022 Sep 16;13(1):5453. doi: 10.1038/s41467-022-33229-5. PMID:36114190^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Goulet I, Boisvenue S, Mokas S, Mazroui R, Cote J. TDRD3, a novel Tudor domain-containing protein, localizes to cytoplasmic stress granules. Hum Mol Genet. 2008 Oct 1;17(19):3055-74. doi: 10.1093/hmg/ddn203. Epub 2008 Jul , 15. PMID:18632687 doi:10.1093/hmg/ddn203
↑ Cote J, Richard S. Tudor domains bind symmetrical dimethylated arginines. J Biol Chem. 2005 Aug 5;280(31):28476-83. Epub 2005 Jun 6. PMID:15955813 doi:M414328200
↑ Yang Y, Lu Y, Espejo A, Wu J, Xu W, Liang S, Bedford MT. TDRD3 is an effector molecule for arginine-methylated histone marks. Mol Cell. 2010 Dec 22;40(6):1016-23. doi: 10.1016/j.molcel.2010.11.024. PMID:21172665 doi:10.1016/j.molcel.2010.11.024
↑ Liu Y, Iqbal A, Li W, Ni Z, Wang Y, Ramprasad J, Abraham KJ, Zhang M, Zhao DY, Qin S, Loppnau P, Jiang H, Guo X, Brown PJ, Zhen X, Xu G, Mekhail K, Ji X, Bedford MT, Greenblatt JF, Min J. A small molecule antagonist of SMN disrupts the interaction between SMN and RNAP II. Nat Commun. 2022 Sep 16;13(1):5453. doi: 10.1038/s41467-022-33229-5. PMID:36114190 doi:http://dx.doi.org/10.1038/s41467-022-33229-5

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6v9t"

@@ Line 3: / Line 3: @@
 <StructureSection load='6v9t' size='340' side='right'caption='[[6v9t]], [[Resolution|resolution]] 2.15&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6v9t]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6V9T OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6V9T FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6v9t]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6V9T OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6V9T FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=36X:4-METHYL-2,3,4,5,6,7-HEXAHYDRODICYCLOPENTA[B,E]PYRIDIN-8(1H)-IMINE'>36X</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</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]] 2.154&#8491;</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=6v9t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6v9t OCA], [http://pdbe.org/6v9t PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6v9t RCSB], [http://www.ebi.ac.uk/pdbsum/6v9t PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6v9t ProSAT]</span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=36X:4-METHYL-2,3,4,5,6,7-HEXAHYDRODICYCLOPENTA[B,E]PYRIDIN-8(1H)-IMINE'>36X</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</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=6v9t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6v9t OCA], [https://pdbe.org/6v9t PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6v9t RCSB], [https://www.ebi.ac.uk/pdbsum/6v9t PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6v9t ProSAT]</span></td></tr>
 </table>
 == 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>
+[https://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 ==
+Survival of motor neuron (SMN) functions in diverse biological pathways via recognition of symmetric dimethylarginine (Rme2s) on proteins by its Tudor domain, and deficiency of SMN leads to spinal muscular atrophy. Here we report a potent and selective antagonist with a 4-iminopyridine scaffold targeting the Tudor domain of SMN. Our structural and mutagenesis studies indicate that both the aromatic ring and imino groups of compound 1 contribute to its selective binding to SMN. Various on-target engagement assays support that compound 1 specifically recognizes SMN in a cellular context and prevents the interaction of SMN with the R1810me2s of RNA polymerase II subunit POLR2A, resulting in transcription termination and R-loop accumulation mimicking SMN depletion. Thus, in addition to the antisense, RNAi and CRISPR/Cas9 techniques, potent SMN antagonists could be used as an efficient tool to understand the biological functions of SMN.
+A small molecule antagonist of SMN disrupts the interaction between SMN and RNAP II.,Liu Y, Iqbal A, Li W, Ni Z, Wang Y, Ramprasad J, Abraham KJ, Zhang M, Zhao DY, Qin S, Loppnau P, Jiang H, Guo X, Brown PJ, Zhen X, Xu G, Mekhail K, Ji X, Bedford MT, Greenblatt JF, Min J Nat Commun. 2022 Sep 16;13(1):5453. doi: 10.1038/s41467-022-33229-5. PMID:36114190<ref>PMID:36114190</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 6v9t" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Arrowsmith, C H]]
+[[Category: Arrowsmith CH]]
-[[Category: Bountra, C]]
+[[Category: Bountra C]]
-[[Category: Edwards, A M]]
+[[Category: Edwards AM]]
-[[Category: Li, W]]
+[[Category: Li W]]
-[[Category: Min, J]]
+[[Category: Min J]]
-[[Category: Structural genomic]]
+[[Category: Tempel W]]
-[[Category: Tempel, W]]
-[[Category: Sgc]]
-[[Category: Transferase]]

6v9t

From Proteopedia

Current revision

Tudor domain of TDRD3 in complex with a small molecule

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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