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| | <StructureSection load='6pai' size='340' side='right'caption='[[6pai]], [[Resolution|resolution]] 2.90Å' scene=''> | | <StructureSection load='6pai' size='340' side='right'caption='[[6pai]], [[Resolution|resolution]] 2.90Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6pai]] is a 4 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=6PAI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6PAI FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6pai]] is a 4 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=6PAI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6PAI FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=O6M:3-cyano-N-(3-cyano-4-methyl-1H-indol-7-yl)benzene-1-sulfonamide'>O6M</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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]] 2.9Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DDB1, XAP1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), DCAF15, C19orf72 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), DKFZp781I1140 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), DDA1, C19orf58, PCIA1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=O6M:3-cyano-N-(3-cyano-4-methyl-1H-indol-7-yl)benzene-1-sulfonamide'>O6M</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=6pai FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pai OCA], [http://pdbe.org/6pai PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6pai RCSB], [http://www.ebi.ac.uk/pdbsum/6pai PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6pai ProSAT]</span></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=6pai FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pai OCA], [https://pdbe.org/6pai PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6pai RCSB], [https://www.ebi.ac.uk/pdbsum/6pai PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6pai ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/DDA1_HUMAN DDA1_HUMAN]] May be involved in ubiquitination and subsequent proteasomal degradation of target proteins. Component of the DDD-E2 complexes which may provide a platform for interaction with CUL4A and WD repeat proteins.<ref>PMID:17452440</ref> [[http://www.uniprot.org/uniprot/DDB1_HUMAN DDB1_HUMAN]] Required for DNA repair. Binds to DDB2 to form the UV-damaged DNA-binding protein complex (the UV-DDB complex). The UV-DDB complex may recognize UV-induced DNA damage and recruit proteins of the nucleotide excision repair pathway (the NER pathway) to initiate DNA repair. The UV-DDB complex preferentially binds to cyclobutane pyrimidine dimers (CPD), 6-4 photoproducts (6-4 PP), apurinic sites and short mismatches. Also appears to function as a component of numerous distinct DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins. The functional specificity of the DCX E3 ubiquitin-protein ligase complex is determined by the variable substrate recognition component recruited by DDB1. DCX(DDB2) (also known as DDB1-CUL4-ROC1, CUL4-DDB-ROC1 and CUL4-DDB-RBX1) may ubiquitinate histone H2A, histone H3 and histone H4 at sites of UV-induced DNA damage. The ubiquitination of histones may facilitate their removal from the nucleosome and promote subsequent DNA repair. DCX(DDB2) also ubiquitinates XPC, which may enhance DNA-binding by XPC and promote NER. DCX(DTL) plays a role in PCNA-dependent polyubiquitination of CDT1 and MDM2-dependent ubiquitination of TP53 in response to radiation-induced DNA damage and during DNA replication. DCX(ERCC8) (the CSA complex) plays a role in transcription-coupled repair (TCR). May also play a role in ubiquitination of CDKN1B/p27kip when associated with CUL4 and SKP2.<ref>PMID:12732143</ref> <ref>PMID:15448697</ref> <ref>PMID:14739464</ref> <ref>PMID:15882621</ref> <ref>PMID:16260596</ref> <ref>PMID:16482215</ref> <ref>PMID:17079684</ref> <ref>PMID:16407242</ref> <ref>PMID:16407252</ref> <ref>PMID:16678110</ref> <ref>PMID:16940174</ref> <ref>PMID:17041588</ref> <ref>PMID:16473935</ref> <ref>PMID:18593899</ref> <ref>PMID:18381890</ref> <ref>PMID:18332868</ref> [[http://www.uniprot.org/uniprot/DCA15_HUMAN DCA15_HUMAN]] May be involved in ubiquitination and degradation through a DBB1-CUL4 E3 protein-ubiquitin ligase.<ref>PMID:16949367</ref> | + | [https://www.uniprot.org/uniprot/DCA15_HUMAN DCA15_HUMAN] May be involved in ubiquitination and degradation through a DBB1-CUL4 E3 protein-ubiquitin ligase.<ref>PMID:16949367</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6pai" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6pai" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[DNA damage-binding protein|DNA damage-binding protein]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Du, X]] | + | [[Category: Du X]] |
| - | [[Category: Volkov, O A]] | + | [[Category: Volkov OA]] |
| - | [[Category: Dcaf15]]
| + | |
| - | [[Category: Ligase]]
| + | |
| - | [[Category: Rbm39]]
| + | |
| - | [[Category: Sulfonamide]]
| + | |
| Structural highlights
Function
DCA15_HUMAN May be involved in ubiquitination and degradation through a DBB1-CUL4 E3 protein-ubiquitin ligase.[1]
Publication Abstract from PubMed
E7820 and indisulam are two examples of aryl sulfonamides that recruit RBM39 to Rbx-Cul4-DDA1-DDB1-DCAF15 E3 ligase complex, leading to its ubiquitination and degradation by the proteasome. To understand their mechanism of action, we performed kinetic analysis on the recruitment of RBM39 to DCAF15 and solved a crystal structure of DDA1-DDB1-DCAF15 in complex with E7820 and the RRM2 domain of RBM39. E7820 packs in a shallow pocket on the surface of DCAF15 and the resulting modified interface binds RBM39 through the alpha1 helix of the RRM2 domain. Our kinetic studies revealed that aryl sulfonamide and RBM39 bind to DCAF15 in a synergistic manner. The structural and kinetic studies confirm aryl sulfonamides as molecular glues in the recruitment of RBM39 and provide a framework for future efforts to utilize DCAF15 to degrade other proteins of interest.
Structural Basis and Kinetic Pathway of RBM39 Recruitment to DCAF15 by a Sulfonamide Molecular Glue E7820.,Du X, Volkov OA, Czerwinski RM, Tan H, Huerta C, Morton ER, Rizzi JP, Wehn PM, Xu R, Nijhawan D, Wallace EM Structure. 2019 Nov 5;27(11):1625-1633.e3. doi: 10.1016/j.str.2019.10.005. PMID:31693911[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Jin J, Arias EE, Chen J, Harper JW, Walter JC. A family of diverse Cul4-Ddb1-interacting proteins includes Cdt2, which is required for S phase destruction of the replication factor Cdt1. Mol Cell. 2006 Sep 1;23(5):709-21. PMID:16949367 doi:http://dx.doi.org/S1097-2765(06)00570-3
- ↑ Du X, Volkov OA, Czerwinski RM, Tan H, Huerta C, Morton ER, Rizzi JP, Wehn PM, Xu R, Nijhawan D, Wallace EM. Structural Basis and Kinetic Pathway of RBM39 Recruitment to DCAF15 by a Sulfonamide Molecular Glue E7820. Structure. 2019 Nov 5;27(11):1625-1633.e3. doi: 10.1016/j.str.2019.10.005. PMID:31693911 doi:http://dx.doi.org/10.1016/j.str.2019.10.005
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