- PDB-6q0v: Structure of DDB1-DDA1-DCAF15 complex bound to tasisulam and RBM39 -
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基本情報
登録情報
データベース: PDB / ID: 6q0v
タイトル
Structure of DDB1-DDA1-DCAF15 complex bound to tasisulam and RBM39
要素
(DDB1- and CUL4-associated factor ...) x 2
DET1- and DDB1-associated protein 1
DNA damage-binding protein 1
RNA-binding protein 39
キーワード
LIGASE / Ubiquitin / homeostasis / targeted protein degradation
機能・相同性
機能・相同性情報
RS domain binding / regulation of natural killer cell activation / positive regulation by virus of viral protein levels in host cell / spindle assembly involved in female meiosis / epigenetic programming in the zygotic pronuclei / U1 snRNP binding / Cul4-RING E3 ubiquitin ligase complex / UV-damage excision repair / regulation of mRNA splicing, via spliceosome / biological process involved in interaction with symbiont ...RS domain binding / regulation of natural killer cell activation / positive regulation by virus of viral protein levels in host cell / spindle assembly involved in female meiosis / epigenetic programming in the zygotic pronuclei / U1 snRNP binding / Cul4-RING E3 ubiquitin ligase complex / UV-damage excision repair / regulation of mRNA splicing, via spliceosome / biological process involved in interaction with symbiont / regulation of mitotic cell cycle phase transition / WD40-repeat domain binding / Cul4A-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / Cul4B-RING E3 ubiquitin ligase complex / immune system process / small molecule binding / negative regulation of reproductive process / negative regulation of developmental process / viral release from host cell / cullin family protein binding / ectopic germ cell programmed cell death / centriolar satellite / proteasomal protein catabolic process / positive regulation of viral genome replication / RNA processing / positive regulation of gluconeogenesis / mRNA Splicing - Major Pathway / RNA splicing / nucleotide-excision repair / Recognition of DNA damage by PCNA-containing replication complex / DNA Damage Recognition in GG-NER / regulation of circadian rhythm / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / Formation of TC-NER Pre-Incision Complex / Dual Incision in GG-NER / Wnt signaling pathway / Formation of Incision Complex in GG-NER / Dual incision in TC-NER / mRNA processing / Gap-filling DNA repair synthesis and ligation in TC-NER / protein polyubiquitination / positive regulation of protein catabolic process / cellular response to UV / microtubule cytoskeleton / rhythmic process / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / site of double-strand break / Neddylation / protein-macromolecule adaptor activity / ubiquitin-dependent protein catabolic process / proteasome-mediated ubiquitin-dependent protein catabolic process / damaged DNA binding / chromosome, telomeric region / protein ubiquitination / nuclear speck / DNA repair / DNA damage response / protein-containing complex binding / negative regulation of apoptotic process / nucleolus / apoptotic process / protein-containing complex / DNA binding / RNA binding / extracellular space / extracellular exosome / nucleoplasm / nucleus / metal ion binding / cytoplasm 類似検索 - 分子機能
DDB1- and CUL4-associated factor 15, WD40 repeat-containing domain / DDB1- and CUL4-associated factor 15 / : / DDB1-and CUL4-substrate receptor 15, WD repeat / Splicing factor, RBM39-like / DET1- and DDB1-associated protein 1, N-terminal / Splicing factor RBM39, linker / DET1- and DDB1-associated protein 1 / Det1 complexing ubiquitin ligase / linker between RRM2 and RRM3 domains in RBM39 protein ...DDB1- and CUL4-associated factor 15, WD40 repeat-containing domain / DDB1- and CUL4-associated factor 15 / : / DDB1-and CUL4-substrate receptor 15, WD repeat / Splicing factor, RBM39-like / DET1- and DDB1-associated protein 1, N-terminal / Splicing factor RBM39, linker / DET1- and DDB1-associated protein 1 / Det1 complexing ubiquitin ligase / linker between RRM2 and RRM3 domains in RBM39 protein / RNA recognition motif domain, eukaryote / RNA recognition motif / Cleavage/polyadenylation specificity factor, A subunit, N-terminal / Cleavage/polyadenylation specificity factor, A subunit, C-terminal / : / Mono-functional DNA-alkylating methyl methanesulfonate N-term / CPSF A subunit region / RRM (RNA recognition motif) domain / RNA recognition motif / RNA recognition motif / Eukaryotic RNA Recognition Motif (RRM) profile. / RNA recognition motif domain / RNA-binding domain superfamily / Nucleotide-binding alpha-beta plait domain superfamily / Alpha-Beta Plaits / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / 2-Layer Sandwich / Alpha Beta 類似検索 - ドメイン・相同性
Chem-P7M / RNA-binding protein 39 / DNA damage-binding protein 1 / DDB1- and CUL4-associated factor 15 / DET1- and DDB1-associated protein 1 類似検索 - 構成要素
National Institutes of Health/National Cancer Institute (NIH/NCI)
R01CA214608
米国
National Institutes of Health/National Cancer Institute (NIH/NCI)
1F32CA232772-01
米国
引用
ジャーナル: Nat Chem Biol / 年: 2020 タイトル: Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15. 著者: Tyler B Faust / Hojong Yoon / Radosław P Nowak / Katherine A Donovan / Zhengnian Li / Quan Cai / Nicholas A Eleuteri / Tinghu Zhang / Nathanael S Gray / Eric S Fischer / 要旨: The investigational drugs E7820, indisulam and tasisulam (aryl-sulfonamides) promote the degradation of the splicing factor RBM39 in a proteasome-dependent mechanism. While the activity critically ...The investigational drugs E7820, indisulam and tasisulam (aryl-sulfonamides) promote the degradation of the splicing factor RBM39 in a proteasome-dependent mechanism. While the activity critically depends on the cullin RING ligase substrate receptor DCAF15, the molecular details remain elusive. Here we present the cryo-EM structure of the DDB1-DCAF15-DDA1 core ligase complex bound to RBM39 and E7820 at a resolution of 4.4 Å, together with crystal structures of engineered subcomplexes. We show that DCAF15 adopts a new fold stabilized by DDA1, and that extensive protein-protein contacts between the ligase and substrate mitigate low affinity interactions between aryl-sulfonamides and DCAF15. Our data demonstrate how aryl-sulfonamides neo-functionalize a shallow, non-conserved pocket on DCAF15 to selectively bind and degrade RBM39 and the closely related splicing factor RBM23 without the requirement for a high-affinity ligand, which has broad implications for the de novo discovery of molecular glue degraders.
A: DNA damage-binding protein 1 B: DDB1- and CUL4-associated factor 15 C: DDB1- and CUL4-associated factor 15 D: RNA-binding protein 39 E: DET1- and DDB1-associated protein 1 ヘテロ分子
解像度: 2.9→46.55 Å / Cor.coef. Fo:Fc: 0.914 / Cor.coef. Fo:Fc free: 0.889 / SU R Cruickshank DPI: 1.053 / 交差検証法: THROUGHOUT / SU R Blow DPI: 0.93 / SU Rfree Blow DPI: 0.328 / SU Rfree Cruickshank DPI: 0.337