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- EMDB-47981: Cryo-EM structure of CSN-N8CUL1 in complex with CSN5i-3 -

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Basic information

Entry
Database: EMDB / ID: EMD-47981
TitleCryo-EM structure of CSN-N8CUL1 in complex with CSN5i-3
Map data
Sample
  • Complex: The COP9 signalosome complex neddylated cullin-1 with CSN5i-3
    • Protein or peptide: x 11 types
  • Ligand: x 2 types
KeywordsCOP9 / COP9 signalosome / signalosome / deneddylation / N8CUL1 / CSN5i-3 / othosteric molecular glue / SIGNALING PROTEIN
Function / homology
Function and homology information


COP9 signalosome assembly / trophectodermal cell proliferation / macrophage migration inhibitory factor binding / regulation of IRE1-mediated unfolded protein response / Parkin-FBXW7-Cul1 ubiquitin ligase complex / exosomal secretion / GTPase inhibitor activity / deNEDDylase activity / protein deneddylation / regulation of protein neddylation ...COP9 signalosome assembly / trophectodermal cell proliferation / macrophage migration inhibitory factor binding / regulation of IRE1-mediated unfolded protein response / Parkin-FBXW7-Cul1 ubiquitin ligase complex / exosomal secretion / GTPase inhibitor activity / deNEDDylase activity / protein deneddylation / regulation of protein neddylation / activation of NF-kappaB-inducing kinase activity / eukaryotic translation initiation factor 3 complex / negative regulation of beige fat cell differentiation / cullin-RING-type E3 NEDD8 transferase / NEDD8 transferase activity / COP9 signalosome / cullin-RING ubiquitin ligase complex / Cul7-RING ubiquitin ligase complex / cellular response to chemical stress / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling / protein K27-linked ubiquitination / positive regulation of protein autoubiquitination / RNA polymerase II transcription initiation surveillance / protein neddylation / NEDD8 ligase activity / Hydrolases; Acting on peptide bonds (peptidases) / RHOBTB1 GTPase cycle / metal-dependent deubiquitinase activity / VCB complex / negative regulation of response to oxidative stress / regulation of JNK cascade / regulation of DNA damage response, signal transduction by p53 class mediator / Cul5-RING ubiquitin ligase complex / inner cell mass cell proliferation / ubiquitin-ubiquitin ligase activity / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / SCF ubiquitin ligase complex / Cul2-RING ubiquitin ligase complex / negative regulation of type I interferon production / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / Cul3-RING ubiquitin ligase complex / negative regulation of mitophagy / Cul4A-RING E3 ubiquitin ligase complex / Cul4-RING E3 ubiquitin ligase complex / Prolactin receptor signaling / Cul4B-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / TGF-beta receptor signaling activates SMADs / regulation of proteolysis / response to light stimulus / cullin family protein binding / skeletal muscle cell differentiation / regulation of postsynapse assembly / protein monoubiquitination / anatomical structure morphogenesis / site of DNA damage / : / protein K48-linked ubiquitination / signal transduction in response to DNA damage / Nuclear events stimulated by ALK signaling in cancer / JNK cascade / transcription-coupled nucleotide-excision repair / translation initiation factor activity / positive regulation of TORC1 signaling / regulation of cellular response to insulin stimulus / negative regulation of insulin receptor signaling pathway / intrinsic apoptotic signaling pathway / post-translational protein modification / T cell activation / negative regulation of canonical NF-kappaB signal transduction / animal organ morphogenesis / Regulation of BACH1 activity / MAP3K8 (TPL2)-dependent MAPK1/3 activation / Degradation of CRY and PER proteins / SCF-beta-TrCP mediated degradation of Emi1 / NIK-->noncanonical NF-kB signaling / cellular response to amino acid stimulus / protein modification process / Degradation of DVL / Dectin-1 mediated noncanonical NF-kB signaling / Activation of NF-kappaB in B cells / G1/S transition of mitotic cell cycle / Degradation of GLI1 by the proteasome / Iron uptake and transport / negative regulation of canonical Wnt signaling pathway / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / Negative regulation of NOTCH4 signaling / Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A / Hedgehog 'on' state / Recognition of DNA damage by PCNA-containing replication complex / Vif-mediated degradation of APOBEC3G / FBXL7 down-regulates AURKA during mitotic entry and in early mitosis / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / RING-type E3 ubiquitin transferase / Degradation of beta-catenin by the destruction complex / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / modification-dependent protein catabolic process / DNA Damage Recognition in GG-NER / Evasion by RSV of host interferon responses
Similarity search - Function
COP9 signalosome complex subunit 7, helix I / : / COP9 signalosome complex subunit 7a helix I domain / COP9 signalosome complex subunit 3-like, C-terminal helix / CSN7 helical bundle subdomain / COP9 signalosome, subunit CSN8 / COP9 signalosome complex subunit 4, helix turn helix domain / : / CSN4/RPN5/eIF3a helix turn helix domain / COP9 signalosome complex subunit 3, N-terminal helical repeats ...COP9 signalosome complex subunit 7, helix I / : / COP9 signalosome complex subunit 7a helix I domain / COP9 signalosome complex subunit 3-like, C-terminal helix / CSN7 helical bundle subdomain / COP9 signalosome, subunit CSN8 / COP9 signalosome complex subunit 4, helix turn helix domain / : / CSN4/RPN5/eIF3a helix turn helix domain / COP9 signalosome complex subunit 3, N-terminal helical repeats / COP9 signalosome subunit 6 / : / COP9 signalosome complex subunit 1, C-terminal helix / Cop9 signalosome subunit 5 C-terminal domain / Cop9 signalosome subunit 5 C-terminal domain / Nedd8-like ubiquitin / Eukaryotic translation initiation factor 3 subunit M eIF3m/COP9 signalosome complex subunit 7 COPS7 / : / Cullin alpha+beta domain / Zinc finger, RING-H2-type / RING-H2 zinc finger domain / Cullin protein neddylation domain / : / : / : / : / PSMD12/CSN4, N-terminal / 26S proteasome regulatory subunit Rpn7/COP9 signalosome complex subunit 1 / 26S proteasome regulatory subunit Rpn7, N-terminal / 26S proteasome subunit RPN7 / 26S Proteasome non-ATPase regulatory subunit 12/COP9 signalosome complex subunit 4 / Cullin, conserved site / Cullin family signature. / Cullin repeat-like-containing domain superfamily / Cullin protein, neddylation domain / Cullin / Cullin protein neddylation domain / Cullin, N-terminal / Cullin alpha solenoid domain / PCI/PINT associated module / Cullin / Cullin homology domain / Cullin homology domain superfamily / Cullin family profile. / CSN8/PSMD8/EIF3K / CSN8/PSMD8/EIF3K family / Rpn11/EIF3F, C-terminal / Maintenance of mitochondrial structure and function / : / motif in proteasome subunits, Int-6, Nip-1 and TRIP-15 / PCI domain / Proteasome component (PCI) domain / PCI domain profile. / JAB1/Mov34/MPN/PAD-1 ubiquitin protease / JAB/MPN domain / JAB1/MPN/MOV34 metalloenzyme domain / MPN domain / MPN domain profile. / Zinc finger RING-type profile. / Zinc finger, RING-type / : / Ubiquitin domain signature. / Ubiquitin conserved site / Ubiquitin domain / Ubiquitin family / Ubiquitin homologues / Tetratricopeptide-like helical domain superfamily / Ubiquitin domain profile. / Ubiquitin-like domain / Zinc finger, RING/FYVE/PHD-type / Ubiquitin-like domain superfamily / Winged helix DNA-binding domain superfamily / Winged helix-like DNA-binding domain superfamily
Similarity search - Domain/homology
COP9 signalosome complex subunit 2 / E3 ubiquitin-protein ligase RBX1 / COP9 signalosome complex subunit 1 / Cullin-1 / Ubiquitin-like protein NEDD8 / COP9 signalosome complex subunit 6 / COP9 signalosome complex subunit 5 / COP9 signalosome complex subunit 8 / COP9 signalosome complex subunit 4 / COP9 signalosome complex subunit 7b / COP9 signalosome complex subunit 3
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.03 Å
AuthorsShi H / Zheng N
Funding support United States, 1 items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: Nature / Year: 2026
Title: CSN5i-3 is an orthosteric molecular glue inhibitor of COP9 signalosome.
Authors: Huigang Shi / Xiaorong Wang / Clinton Yu / Haibin Mao / Fenglong Jiao / Merav Braitbard / Ben Shor / Zhongsheng Zhang / Thomas R Hinds / Shiyun Cao / Erkang Fan / Dina Schneidman-Duhovny / ...Authors: Huigang Shi / Xiaorong Wang / Clinton Yu / Haibin Mao / Fenglong Jiao / Merav Braitbard / Ben Shor / Zhongsheng Zhang / Thomas R Hinds / Shiyun Cao / Erkang Fan / Dina Schneidman-Duhovny / Lan Huang / Ning Zheng /
Abstract: Orthosteric inhibitors block enzyme active sites and prevent substrates from binding. Enhancing their specificity through substrate dependence seems inherently unlikely, as their mechanism hinges on ...Orthosteric inhibitors block enzyme active sites and prevent substrates from binding. Enhancing their specificity through substrate dependence seems inherently unlikely, as their mechanism hinges on direct competition rather than selective recognition. Here we show that a molecular glue mechanism unexpectedly imparts substrate-dependent potency to CSN5i-3, an orthosteric inhibitor of the COP9 signalosome (CSN). We first confirm that CSN5i-3 inhibits CSN, which catalyses NEDD8 (N8) deconjugation from the cullin-RING ubiquitin ligases, by occupying the active site of its catalytic subunit, CSN5, and directly competing with the iso-peptide bond substrate. Notably, the orthosteric inhibitor binds free CSN with only micromolar affinity, yet achieves nanomolar potency in blocking its deneddylase activity. Cryogenic electron microscopy structures of the enzyme-substrate-inhibitor complex reveal that active site-engaged CSN5i-3 occludes the substrate iso-peptide linkage while simultaneously extending an N8-binding exosite of CSN5, acting as a molecular glue to cement the N8-CSN5 interaction. The cooperativity of this trimolecular CSN5i-3-N8-CSN5 assembly, in turn, sequesters CSN5i-3 at its binding site, conferring high potency to the orthosteric inhibitor despite its low affinity for the free enzyme. Together, our findings highlight the modest affinity requirements of molecule glues for individual target proteins and establish orthosteric molecular glue inhibitors as a new class of substrate-dependent enzyme antagonists.
History
DepositionNov 20, 2024-
Header (metadata) releaseDec 3, 2025-
Map releaseDec 3, 2025-
UpdateFeb 25, 2026-
Current statusFeb 25, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_47981.png

Downloads & links

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Map

FileDownload / File: emd_47981.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 400 pix.
= 330.8 Å		0.83 Å/pix.
x 400 pix.
= 330.8 Å		0.83 Å/pix.
x 400 pix.
= 330.8 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.827 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.08
Minimum - Maximum-0.34571004 - 1.2595248
Average (Standard dev.)0.0077354275 (±0.023912318)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 330.80002 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : The COP9 signalosome complex neddylated cullin-1 with CSN5i-3

EntireName: The COP9 signalosome complex neddylated cullin-1 with CSN5i-3
Components
  • Complex: The COP9 signalosome complex neddylated cullin-1 with CSN5i-3
    • Protein or peptide: COP9 signalosome complex subunit 1
    • Protein or peptide: COP9 signalosome complex subunit 2
    • Protein or peptide: COP9 signalosome complex subunit 3
    • Protein or peptide: COP9 signalosome complex subunit 4
    • Protein or peptide: COP9 signalosome complex subunit 5
    • Protein or peptide: COP9 signalosome complex subunit 6
    • Protein or peptide: COP9 signalosome complex subunit 7b
    • Protein or peptide: COP9 signalosome complex subunit 8
    • Protein or peptide: NEDD8
    • Protein or peptide: Cullin-1
    • Protein or peptide: E3 ubiquitin-protein ligase RBX1
  • Ligand: 3-(difluoromethyl)-N-{6-[(5S,6S)-6-hydroxy-6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepin-5-yl][1,1'-biphenyl]-3-yl}-1-(propan-2-yl)-1H-pyrazole-5-carboxamide
  • Ligand: ZINC ION

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Supramolecule #1: The COP9 signalosome complex neddylated cullin-1 with CSN5i-3

SupramoleculeName: The COP9 signalosome complex neddylated cullin-1 with CSN5i-3
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#11
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: COP9 signalosome complex subunit 1

MacromoleculeName: COP9 signalosome complex subunit 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 55.606496 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MPLPVQVFNL QGAVEPMQID VDPQEDPQNA PDVNYVVENP SLDLEQYAAS YSGLMRIERL QFIADHCPTL RVEALKMALS FVQRTFNVD MYEEIHRKLS EATRSSLREL QNAPDAIPES GVEPPALDTA WVEATRKKAL LKLEKLDTDL KNYKGNSIKE S IRRGHDDL ...String:
MPLPVQVFNL QGAVEPMQID VDPQEDPQNA PDVNYVVENP SLDLEQYAAS YSGLMRIERL QFIADHCPTL RVEALKMALS FVQRTFNVD MYEEIHRKLS EATRSSLREL QNAPDAIPES GVEPPALDTA WVEATRKKAL LKLEKLDTDL KNYKGNSIKE S IRRGHDDL GDHYLDCGDL SNALKCYSRA RDYCTSAKHV INMCLNVIKV SVYLQNWSHV LSYVSKAEST PEIAEQRGER DS QTQAILT KLKCAAGLAE LAARKYKQAA KCLLLASFDH CDFPELLSPS NVAIYGGLCA LATFDRQELQ RNVISSSSFK LFL ELEPQV RDIIFKFYES KYASCLKMLD EMKDNLLLDM YLAPHVRTLY TQIRNRALIQ YFSPYVSADM HRMAAAFNTT VAAL EDELT QLILEGLISA RVDSHSKILY ARDVDQRSTT FEKSLLMGKE FQRRAKAMML RAAVLRNQIH VKSPPREGSQ GELTP ANSQ SRMSTNM

UniProtKB: COP9 signalosome complex subunit 1

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Macromolecule #2: COP9 signalosome complex subunit 2

MacromoleculeName: COP9 signalosome complex subunit 2 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 51.66457 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MSDMEDDFMC DDEEDYDLEY SEDSNSEPNV DLENQYYNSK ALKEDDPKAA LSSFQKVLEL EGEKGEWGFK ALKQMIKINF KLTNFPEMM NRYKQLLTYI RSAVTRNYSE KSINSILDYI STSKQMDLLQ EFYETTLEAL KDAKNDRLWF KTNTKLGKLY L EREEYGKL ...String:
MSDMEDDFMC DDEEDYDLEY SEDSNSEPNV DLENQYYNSK ALKEDDPKAA LSSFQKVLEL EGEKGEWGFK ALKQMIKINF KLTNFPEMM NRYKQLLTYI RSAVTRNYSE KSINSILDYI STSKQMDLLQ EFYETTLEAL KDAKNDRLWF KTNTKLGKLY L EREEYGKL QKILRQLHQS CQTDDGEDDL KKGTQLLEIY ALEIQMYTAQ KNNKKLKALY EQSLHIKSAI PHPLIMGVIR EC GGKMHLR EGEFEKAHTD FFEAFKNYDE SGSPRRTTCL KYLVLANMLM KSGINPFDSQ EAKPYKNDPE ILAMTNLVSA YQN NDITEF EKILKTNHSN IMDDPFIREH IEELLRNIRT QVLIKLIKPY TRIHIPFISK ELNIDVADVE SLLVQCILDN TIHG RIDQV NQLLELDHQK RGGARYTALD KWTNQLNSLN QAVVSKLA

UniProtKB: COP9 signalosome complex subunit 2

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Macromolecule #3: COP9 signalosome complex subunit 3

MacromoleculeName: COP9 signalosome complex subunit 3 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 47.924008 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MASALEQFVN SVRQLSAQGQ MTQLCELINK SGELLAKNLS HLDTVLGALD VQEHSLGVLA VLFVKFSMPS VPDFETLFSQ VQLFISTCN GEHIRYATDT FAGLCHQLTN ALVERKQPLR GIGILKQAID KMQMNTNQLT SIHADLCQLC LLAKCFKPAL P YLDVDMMD ...String:
MASALEQFVN SVRQLSAQGQ MTQLCELINK SGELLAKNLS HLDTVLGALD VQEHSLGVLA VLFVKFSMPS VPDFETLFSQ VQLFISTCN GEHIRYATDT FAGLCHQLTN ALVERKQPLR GIGILKQAID KMQMNTNQLT SIHADLCQLC LLAKCFKPAL P YLDVDMMD ICKENGAYDA KHFLCYYYYG GMIYTGLKNF ERALYFYEQA ITTPAMAVSH IMLESYKKYI LVSLILLGKV QQ LPKYTSQ IVGRFIKPLS NAYHELAQVY STNNPSELRN LVNKHSETFT RDNNMGLVKQ CLSSLYKKNI QRLTKTFLTL SLQ DMASRV QLSGPQEAEK YVLHMIEDGE IFASINQKDG MVSFHDNPEK YNNPAMLHNI DQEMLKCIEL DERLKAMDQE ITVN PQFVQ KSMGSQEDDS GNKPSSYS

UniProtKB: COP9 signalosome complex subunit 3

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Macromolecule #4: COP9 signalosome complex subunit 4

MacromoleculeName: COP9 signalosome complex subunit 4 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 46.322688 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MAAAVRQDLA QLMNSSGSHK DLAGKYRQIL EKAIQLSGAE QLEALKAFVE AMVNENVSLV ISRQLLTDFC THLPNLPDST AKEIYHFTL EKIQPRVISF EEQVASIRQH LASIYEKEED WRNAAQVLVG IPLETGQKQY NVDYKLETYL KIARLYLEDD D PVQAEAYI ...String:
MAAAVRQDLA QLMNSSGSHK DLAGKYRQIL EKAIQLSGAE QLEALKAFVE AMVNENVSLV ISRQLLTDFC THLPNLPDST AKEIYHFTL EKIQPRVISF EEQVASIRQH LASIYEKEED WRNAAQVLVG IPLETGQKQY NVDYKLETYL KIARLYLEDD D PVQAEAYI NRASLLQNES TNEQLQIHYK VCYARVLDYR RKFIEAAQRY NELSYKTIVH ESERLEALKH ALHCTILASA GQ QRSRMLA TLFKDERCQQ LAAYGILEKM YLDRIIRGNQ LQEFAAMLMP HQKATTADGS SILDRAVIEH NLLSASKLYN NIT FEELGA LLEIPAAKAE KIASQMITEG RMNGFIDQID GIVHFETREA LPTWDKQIQS LCFQVNNLLE KISQTAPEWT AQAM EAQMA Q

UniProtKB: COP9 signalosome complex subunit 4

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Macromolecule #5: COP9 signalosome complex subunit 5

MacromoleculeName: COP9 signalosome complex subunit 5 / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO / EC number: Hydrolases; Acting on peptide bonds (peptidases)
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 37.621742 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MAASGSGMAQ KTWELANNMQ EAQSIDEIYK YDKKQQQEIL AAKPWTKDHH YFKYCKISAL ALLKMVMHAR SGGNLEVMGL MLGKVDGET MIIMDSFALP VEGTETRVNA QAAAYEYMAA YIENAKQVGR LENAIGWYHS HPGYGCWLSG IDVSTQMLNQ Q FQEPFVAV ...String:
MAASGSGMAQ KTWELANNMQ EAQSIDEIYK YDKKQQQEIL AAKPWTKDHH YFKYCKISAL ALLKMVMHAR SGGNLEVMGL MLGKVDGET MIIMDSFALP VEGTETRVNA QAAAYEYMAA YIENAKQVGR LENAIGWYHS HPGYGCWLSG IDVSTQMLNQ Q FQEPFVAV VIDPTRTISA GKVNLGAFRT YPKGYKPPDE GPSEYQTIPL NKIEDFGVHC KQYYALEVSY FKSSLDRKLL EL LWNKYWV NTLSSSSLLT NADYTTGQVF DLSEKLEQSE AQLGRGSFML GLETHDRKSE DKLAKATRDS CKTTIEAIHG LMS QVIKDK LFNQINIS

UniProtKB: COP9 signalosome complex subunit 5

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Macromolecule #6: COP9 signalosome complex subunit 6

MacromoleculeName: COP9 signalosome complex subunit 6 / type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 36.203398 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MAAAAAAAAA TNGTGGSSGM EVDAAVVPSV MACGVTGSVS VALHPLVILN ISDHWIRMRS QEGRPVQVIG ALIGKQEGRN IEVMNSFEL LSHTVEEKII IDKEYYYTKE EQFKQVFKEL EFLGWYTTGG PPDPSDIHVH KQVCEIIESP LFLKLNPMTK H TDLPVSVF ...String:
MAAAAAAAAA TNGTGGSSGM EVDAAVVPSV MACGVTGSVS VALHPLVILN ISDHWIRMRS QEGRPVQVIG ALIGKQEGRN IEVMNSFEL LSHTVEEKII IDKEYYYTKE EQFKQVFKEL EFLGWYTTGG PPDPSDIHVH KQVCEIIESP LFLKLNPMTK H TDLPVSVF ESVIDIINGE ATMLFAELTY TLATEEAERI GVDHVARMTA TGSGENSTVA EHLIAQHSAI KMLHSRVKLI LE YVKASEA GEVPFNHEIL REAYALCHCL PVLSTDKFKT DFYDQCNDVG LMAYLGTITK TCNTMNQFVN KFNVLYDRQG IGR RMRGLF F

UniProtKB: COP9 signalosome complex subunit 6

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Macromolecule #7: COP9 signalosome complex subunit 7b

MacromoleculeName: COP9 signalosome complex subunit 7b / type: protein_or_peptide / ID: 7 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 29.656928 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MAGEQKPSSN LLEQFILLAK GTSGSALTAL ISQVLEAPGV YVFGELLELA NVQELAEGAN AAYLQLLNLF AYGTYPDYIA NKESLPELS TAQQNKLKHL TIVSLASRMK CIPYSVLLKD LEMRNLRELE DLIIEAVYTD IIQGKLDQRN QLLEVDFCIG R DIRKKDIN ...String:
MAGEQKPSSN LLEQFILLAK GTSGSALTAL ISQVLEAPGV YVFGELLELA NVQELAEGAN AAYLQLLNLF AYGTYPDYIA NKESLPELS TAQQNKLKHL TIVSLASRMK CIPYSVLLKD LEMRNLRELE DLIIEAVYTD IIQGKLDQRN QLLEVDFCIG R DIRKKDIN NIVKTLHEWC DGCEAVLLGI EQQVLRANQY KENHNRTQQQ VEAEVTNIKK TLKATASSSA QEMEQQLAER EC PPHAEQR QPTKKMSKVK GLVSSRH

UniProtKB: COP9 signalosome complex subunit 7b

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Macromolecule #8: COP9 signalosome complex subunit 8

MacromoleculeName: COP9 signalosome complex subunit 8 / type: protein_or_peptide / ID: 8 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.245543 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MPVAVMAESA FSFKKLLDQC ENQELEAPGG IATPPVYGQL LALYLLHNDM NNARYLWKRI PPAIKSANSE LGGIWSVGQR IWQRDFPGI YTTINAHQWS ETVQPIMEAL RDATRRRAFA LVSQAYTSII ADDFAAFVGL PVEEAVKGIL EQGWQADSTT R MVLPRKPV ...String:
MPVAVMAESA FSFKKLLDQC ENQELEAPGG IATPPVYGQL LALYLLHNDM NNARYLWKRI PPAIKSANSE LGGIWSVGQR IWQRDFPGI YTTINAHQWS ETVQPIMEAL RDATRRRAFA LVSQAYTSII ADDFAAFVGL PVEEAVKGIL EQGWQADSTT R MVLPRKPV AGALDVSFNK FIPLSEPAPV PPIPNEQQLA RLTDYVAFLE N

UniProtKB: COP9 signalosome complex subunit 8

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Macromolecule #9: NEDD8

MacromoleculeName: NEDD8 / type: protein_or_peptide / ID: 9 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 9.086562 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MLIKVKTLTG KEIEIDIEPT DKVERIKERV EEKEGIPPQQ QRLIYSGKQM NDEKTAADYK ILGGSVLHLV LALRGGGGLR Q

UniProtKB: Ubiquitin-like protein NEDD8

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Macromolecule #10: Cullin-1

MacromoleculeName: Cullin-1 / type: protein_or_peptide / ID: 10 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 89.800367 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MSSTRSQNPH GLKQIGLDQI WDDLRAGIQQ VYTRQSMAKS RYMELYTHVY NYCTSVHQSN QARGAGVPPS KSKKGQTPGG AQFVGLELY KRLKEFLKNY LTNLLKDGED LMDESVLKFY TQQWEDYRFS SKVLNGICAY LNRHWVRREC DEGRKGIYEI Y SLALVTWR ...String:
MSSTRSQNPH GLKQIGLDQI WDDLRAGIQQ VYTRQSMAKS RYMELYTHVY NYCTSVHQSN QARGAGVPPS KSKKGQTPGG AQFVGLELY KRLKEFLKNY LTNLLKDGED LMDESVLKFY TQQWEDYRFS SKVLNGICAY LNRHWVRREC DEGRKGIYEI Y SLALVTWR DCLFRPLNKQ VTNAVLKLIE KERNGETINT RLISGVVQSY VELGLNEDDA FAKGPTLTVY KESFESQFLA DT ERFYTRE STEFLQQNPV TEYMKKAEAR LLEEQRRVQV YLHESTQDEL ARKCEQVLIE KHLEIFHTEF QNLLDADKNE DLG RMYNLV SRIQDGLGEL KKLLETHIHN QGLAAIEKCG EAALNDPKMY VQTVLDVHKK YNALVMSAFN NDAGFVAALD KACG RFINN NAVTKMAQSS SKSPELLARY CDSLLKKSSK NPEEAELEDT LNQVMVVFKY IEDKDVFQKF YAKMLAKRLV HQNSA SDDA EASMISKLKQ ACGFEYTSKL QRMFQDIGVS KDLNEQFKKH LTNSEPLDLD FSIQVLSSGS WPFQQSCTFA LPSELE RSY QRFTAFYASR HSGRKLTWLY QLSKGELVTN CFKNRYTLQA STFQMAILLQ YNTEDAYTVQ QLTDSTQIKM DILAQVL QI LLKSKLLVLE DENANVDEVE LKPDTLIKLY LGYKNKKLRV NINVPMKTEQ KQEQETTHKN IEEDRKLLIQ AAIVRIMK M RKVLKHQQLL GEVLTQLSSR FKPRVPVIKK CIDILIEKEY LERVDGEKDT YSYLA

UniProtKB: Cullin-1

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Macromolecule #11: E3 ubiquitin-protein ligase RBX1

MacromoleculeName: E3 ubiquitin-protein ligase RBX1 / type: protein_or_peptide / ID: 11 / Number of copies: 1 / Enantiomer: LEVO / EC number: RING-type E3 ubiquitin transferase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 12.289977 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MAAAMDVDTP SGTNSGAGKK RFEVKKWNAV ALWAWDIVVD NCAICRNHIM DLCIECQANQ ASATSEECTV AWGVCNHAFH FHCISRWLK TRQVCPLDNR EWEFQKYGH

UniProtKB: E3 ubiquitin-protein ligase RBX1

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Macromolecule #12: 3-(difluoromethyl)-N-{6-[(5S,6S)-6-hydroxy-6,7,8,9-tetrahydro-5H-...

MacromoleculeName: 3-(difluoromethyl)-N-{6-[(5S,6S)-6-hydroxy-6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepin-5-yl][1,1'-biphenyl]-3-yl}-1-(propan-2-yl)-1H-pyrazole-5-carboxamide
type: ligand / ID: 12 / Number of copies: 1 / Formula: 6LT
Molecular weightTheoretical: 505.559 Da
Chemical component information

ChemComp-6LT:
3-(difluoromethyl)-N-{6-[(5S,6S)-6-hydroxy-6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepin-5-yl][1,1'-biphenyl]-3-yl}-1-(propan-2-yl)-1H-pyrazole-5-carboxamide

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Macromolecule #13: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 13 / Number of copies: 4 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
GridModel: UltrAuFoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.0 µm / Nominal defocus min: 0.8 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER / Details: Ab-initio reconstruction
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 3.03 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 174577
Initial angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: cryoSPARC
Final angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: cryoSPARC

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