6ud7: Difference between revisions
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The | ==Crystal structure of full-length human DCAF15-DDB1(deltaBPB)-DDA1-RBM39 in complex with indisulam== | ||
<StructureSection load='6ud7' size='340' side='right'caption='[[6ud7]], [[Resolution|resolution]] 2.30Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6ud7]] 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=6UD7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6UD7 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EF6:~{N}1-(3-chloranyl-1~{H}-indol-7-yl)benzene-1,4-disulfonamide'>EF6</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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=6ud7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ud7 OCA], [https://pdbe.org/6ud7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ud7 RCSB], [https://www.ebi.ac.uk/pdbsum/6ud7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ud7 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[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;"> | |||
== Publication Abstract from PubMed == | |||
The anticancer agent indisulam inhibits cell proliferation by causing degradation of RBM39, an essential mRNA splicing factor. Indisulam promotes an interaction between RBM39 and the DCAF15 E3 ligase substrate receptor, leading to RBM39 ubiquitination and proteasome-mediated degradation. To delineate the precise mechanism by which indisulam mediates the DCAF15-RBM39 interaction, we solved the DCAF15-DDB1-DDA1-indisulam-RBM39(RRM2) complex structure to a resolution of 2.3 A. DCAF15 has a distinct topology that embraces the RBM39(RRM2) domain largely via non-polar interactions, and indisulam binds between DCAF15 and RBM39(RRM2), coordinating additional interactions between the two proteins. Studies with RBM39 point mutants and indisulam analogs validated the structural model and defined the RBM39 alpha-helical degron motif. The degron is found only in RBM23 and RBM39, and only these proteins were detectably downregulated in indisulam-treated HCT116 cells. This work further explains how indisulam induces RBM39 degradation and defines the challenge of harnessing DCAF15 to degrade additional targets. | |||
Structural basis of indisulam-mediated RBM39 recruitment to DCAF15 E3 ligase complex.,Bussiere DE, Xie L, Srinivas H, Shu W, Burke A, Be C, Zhao J, Godbole A, King D, Karki RG, Hornak V, Xu F, Cobb J, Carte N, Frank AO, Frommlet A, Graff P, Knapp M, Fazal A, Okram B, Jiang S, Michellys PY, Beckwith R, Voshol H, Wiesmann C, Solomon JM, Paulk J Nat Chem Biol. 2020 Jan;16(1):15-23. doi: 10.1038/s41589-019-0411-6. Epub 2019, Dec 9. PMID:31819272<ref>PMID:31819272</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6ud7" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[DNA damage-binding protein|DNA damage-binding protein]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Bussiere DE]] | |||
[[Category: Knapp M]] | |||
[[Category: Shu W]] | |||
[[Category: Xie L]] | |||
Latest revision as of 12:14, 9 October 2024
Crystal structure of full-length human DCAF15-DDB1(deltaBPB)-DDA1-RBM39 in complex with indisulamCrystal structure of full-length human DCAF15-DDB1(deltaBPB)-DDA1-RBM39 in complex with indisulam
Structural highlights
FunctionDCA15_HUMAN May be involved in ubiquitination and degradation through a DBB1-CUL4 E3 protein-ubiquitin ligase.[1] Publication Abstract from PubMedThe anticancer agent indisulam inhibits cell proliferation by causing degradation of RBM39, an essential mRNA splicing factor. Indisulam promotes an interaction between RBM39 and the DCAF15 E3 ligase substrate receptor, leading to RBM39 ubiquitination and proteasome-mediated degradation. To delineate the precise mechanism by which indisulam mediates the DCAF15-RBM39 interaction, we solved the DCAF15-DDB1-DDA1-indisulam-RBM39(RRM2) complex structure to a resolution of 2.3 A. DCAF15 has a distinct topology that embraces the RBM39(RRM2) domain largely via non-polar interactions, and indisulam binds between DCAF15 and RBM39(RRM2), coordinating additional interactions between the two proteins. Studies with RBM39 point mutants and indisulam analogs validated the structural model and defined the RBM39 alpha-helical degron motif. The degron is found only in RBM23 and RBM39, and only these proteins were detectably downregulated in indisulam-treated HCT116 cells. This work further explains how indisulam induces RBM39 degradation and defines the challenge of harnessing DCAF15 to degrade additional targets. Structural basis of indisulam-mediated RBM39 recruitment to DCAF15 E3 ligase complex.,Bussiere DE, Xie L, Srinivas H, Shu W, Burke A, Be C, Zhao J, Godbole A, King D, Karki RG, Hornak V, Xu F, Cobb J, Carte N, Frank AO, Frommlet A, Graff P, Knapp M, Fazal A, Okram B, Jiang S, Michellys PY, Beckwith R, Voshol H, Wiesmann C, Solomon JM, Paulk J Nat Chem Biol. 2020 Jan;16(1):15-23. doi: 10.1038/s41589-019-0411-6. Epub 2019, Dec 9. PMID:31819272[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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