- EMDB-15284: Cryo-EM structure of USP1-UAF1 bound to FANCI and mono-ubiquitina... -
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基本情報
登録情報
データベース: EMDB / ID: EMD-15284
タイトル
Cryo-EM structure of USP1-UAF1 bound to FANCI and mono-ubiquitinated FANCD2 without ML323 (consensus reconstruction)
マップデータ
Globally sharpened map
試料
複合体: USP1(C90S)-UAF1 bound to FANCI and mono-ubiquitinated FANCD2 with dsDNA
複合体: Fanconi anemia group I protein, Fanconi anemia group D2 protein with ubiquitin conjugated to K561, Ubiquitin carboxyl-terminal hydrolase 1, WD repeat-containing protein 48
regulation of protein monoubiquitination / positive regulation of error-prone translesion synthesis / Signaling by cytosolic PDGFRA and PDGFRB fusion proteins / regulation of CD40 signaling pathway / double-strand break repair involved in meiotic recombination / gamete generation / monoubiquitinated protein deubiquitination / homologous chromosome pairing at meiosis / regulation of regulatory T cell differentiation / neuronal stem cell population maintenance ...regulation of protein monoubiquitination / positive regulation of error-prone translesion synthesis / Signaling by cytosolic PDGFRA and PDGFRB fusion proteins / regulation of CD40 signaling pathway / double-strand break repair involved in meiotic recombination / gamete generation / monoubiquitinated protein deubiquitination / homologous chromosome pairing at meiosis / regulation of regulatory T cell differentiation / neuronal stem cell population maintenance / brain morphogenesis / deubiquitinase activator activity / mitotic intra-S DNA damage checkpoint signaling / DNA repair complex / skeletal system morphogenesis / skin development / seminiferous tubule development / homeostasis of number of cells / protein deubiquitination / embryonic organ development / single fertilization / interstrand cross-link repair / positive regulation of double-strand break repair via homologous recombination / regulation of DNA repair / response to UV / condensed chromosome / DNA polymerase binding / Maturation of protein E / Maturation of protein E / ER Quality Control Compartment (ERQC) / Myoclonic epilepsy of Lafora / FLT3 signaling by CBL mutants / Prevention of phagosomal-lysosomal fusion / IRAK2 mediated activation of TAK1 complex / Alpha-protein kinase 1 signaling pathway / Glycogen synthesis / IRAK1 recruits IKK complex / IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation / Membrane binding and targetting of GAG proteins / Endosomal Sorting Complex Required For Transport (ESCRT) / Regulation of TBK1, IKKε (IKBKE)-mediated activation of IRF3, IRF7 / Negative regulation of FLT3 / PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 / Regulation of TBK1, IKKε-mediated activation of IRF3, IRF7 upon TLR3 ligation / Constitutive Signaling by NOTCH1 HD Domain Mutants / IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation / NOTCH2 Activation and Transmission of Signal to the Nucleus / TICAM1,TRAF6-dependent induction of TAK1 complex / TICAM1-dependent activation of IRF3/IRF7 / APC/C:Cdc20 mediated degradation of Cyclin B / Regulation of FZD by ubiquitination / Downregulation of ERBB4 signaling / APC-Cdc20 mediated degradation of Nek2A / p75NTR recruits signalling complexes / InlA-mediated entry of Listeria monocytogenes into host cells / TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling / TRAF6-mediated induction of TAK1 complex within TLR4 complex / Regulation of pyruvate metabolism / Regulation of innate immune responses to cytosolic DNA / NF-kB is activated and signals survival / Downregulation of ERBB2:ERBB3 signaling / Pexophagy / NRIF signals cell death from the nucleus / VLDLR internalisation and degradation / Regulation of PTEN localization / Activated NOTCH1 Transmits Signal to the Nucleus / Synthesis of active ubiquitin: roles of E1 and E2 enzymes / Regulation of BACH1 activity / MAP3K8 (TPL2)-dependent MAPK1/3 activation / TICAM1, RIP1-mediated IKK complex recruitment / positive regulation of epithelial cell proliferation / Translesion synthesis by REV1 / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / Translesion synthesis by POLK / InlB-mediated entry of Listeria monocytogenes into host cell / Downregulation of TGF-beta receptor signaling / Josephin domain DUBs / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / Regulation of activated PAK-2p34 by proteasome mediated degradation / ubiquitin binding / Translesion synthesis by POLI / IKK complex recruitment mediated by RIP1 / Gap-filling DNA repair synthesis and ligation in GG-NER / positive regulation of protein ubiquitination / PINK1-PRKN Mediated Mitophagy / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / TNFR1-induced NF-kappa-B signaling pathway / skeletal system development / Autodegradation of Cdh1 by Cdh1:APC/C / APC/C:Cdc20 mediated degradation of Securin / N-glycan trimming in the ER and Calnexin/Calreticulin cycle / TCF dependent signaling in response to WNT / response to gamma radiation / Asymmetric localization of PCP proteins / Regulation of NF-kappa B signaling / Ubiquitin-dependent degradation of Cyclin D / SCF-beta-TrCP mediated degradation of Emi1 / NIK-->noncanonical NF-kB signaling / activated TAK1 mediates p38 MAPK activation / Negative regulators of DDX58/IFIH1 signaling 類似検索 - 分子機能
Ubiquitin carboxyl-terminal hydrolase 1 / Polyubiquitin-C / WD repeat-containing protein 48 / Fanconi anemia group D2 protein / Fanconi anemia group I protein 類似検索 - 構成要素
ジャーナル: Sci Adv / 年: 2022 タイトル: Cryo-EM reveals a mechanism of USP1 inhibition through a cryptic binding site. 著者: Martin L Rennie / Connor Arkinson / Viduth K Chaugule / Helen Walden / 要旨: Repair of DNA damage is critical to genomic integrity and frequently disrupted in cancers. Ubiquitin-specific protease 1 (USP1), a nucleus-localized deubiquitinase, lies at the interface of multiple ...Repair of DNA damage is critical to genomic integrity and frequently disrupted in cancers. Ubiquitin-specific protease 1 (USP1), a nucleus-localized deubiquitinase, lies at the interface of multiple DNA repair pathways and is a promising drug target for certain cancers. Although multiple inhibitors of this enzyme, including one in phase 1 clinical trials, have been established, their binding mode is unknown. Here, we use cryo-electron microscopy to study an assembled enzyme-substrate-inhibitor complex of USP1 and the well-established inhibitor, ML323. Achieving 2.5-Å resolution, with and without ML323, we find an unusual binding mode in which the inhibitor disrupts part of the hydrophobic core of USP1. The consequent conformational changes in the secondary structure lead to subtle rearrangements in the active site that underlie the mechanism of inhibition. These structures provide a platform for structure-based drug design targeting USP1.
全体 : USP1(C90S)-UAF1 bound to FANCI and mono-ubiquitinated FANCD2 with...
全体
名称: USP1(C90S)-UAF1 bound to FANCI and mono-ubiquitinated FANCD2 with dsDNA
要素
複合体: USP1(C90S)-UAF1 bound to FANCI and mono-ubiquitinated FANCD2 with dsDNA
複合体: Fanconi anemia group I protein, Fanconi anemia group D2 protein with ubiquitin conjugated to K561, Ubiquitin carboxyl-terminal hydrolase 1, WD repeat-containing protein 48
超分子 #1: USP1(C90S)-UAF1 bound to FANCI and mono-ubiquitinated FANCD2 with...
超分子
名称: USP1(C90S)-UAF1 bound to FANCI and mono-ubiquitinated FANCD2 with dsDNA タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1-#6
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超分子 #2: Fanconi anemia group I protein, Fanconi anemia group D2 protein w...
超分子
名称: Fanconi anemia group I protein, Fanconi anemia group D2 protein with ubiquitin conjugated to K561, Ubiquitin carboxyl-terminal hydrolase 1, WD repeat-containing protein 48 タイプ: complex / ID: 2 / 親要素: 1 / 含まれる分子: #1-#6
由来(天然)
生物種: Homo sapiens (ヒト)
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分子 #1: Fanconi anemia group I protein
分子
名称: Fanconi anemia group I protein / タイプ: protein_or_peptide / ID: 1 / コピー数: 1 / 光学異性体: LEVO