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- EMDB-25214: Cryo-EM structure of Drosophila Integrator cleavage module (IntS4... -

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Basic information

Entry
Database: EMDB / ID: EMD-25214
TitleCryo-EM structure of Drosophila Integrator cleavage module (IntS4-IntS9-IntS11) in complex with IP6
Map data
Sample
  • Complex: Integrator cleavage module with inositol hexakisphosphate
    • Protein or peptide: Integrator complex subunit 4
    • Protein or peptide: Integrator complex subunit 11
    • Protein or peptide: Integrator complex subunit 9
  • Ligand: ZINC ION
  • Ligand: INOSITOL HEXAKISPHOSPHATE
Keywordsintegrator / inositol hexakisphosphate / NUCLEASE
Function / homology
Function and homology information


RNA polymerase II transcribes snRNA genes / snRNA 3'-end processing / snRNA processing / INTAC complex / integrator complex / Hydrolases; Acting on ester bonds; Endoribonucleases producing 3'-phosphomonoesters / RNA polymerase II transcription initiation surveillance / inositol hexakisphosphate binding / negative regulation of BMP signaling pathway / RNA endonuclease activity ...RNA polymerase II transcribes snRNA genes / snRNA 3'-end processing / snRNA processing / INTAC complex / integrator complex / Hydrolases; Acting on ester bonds; Endoribonucleases producing 3'-phosphomonoesters / RNA polymerase II transcription initiation surveillance / inositol hexakisphosphate binding / negative regulation of BMP signaling pathway / RNA endonuclease activity / nucleus / cytoplasm / cytosol
Similarity search - Function
: / INTS4 8 helical bundle domain / Integrator subunit 4 family C-terminal Ig-like domain / Integrator complex subunit 9 / : / Integrator IntS9, C-terminal domain / Integrator complex subunit 11, MBL-fold / : / Integrator IntS11, C-terminal domain / Metallo-beta-lactamase superfamily domain ...: / INTS4 8 helical bundle domain / Integrator subunit 4 family C-terminal Ig-like domain / Integrator complex subunit 9 / : / Integrator IntS9, C-terminal domain / Integrator complex subunit 11, MBL-fold / : / Integrator IntS11, C-terminal domain / Metallo-beta-lactamase superfamily domain / : / Beta-Casp domain / Beta-Casp domain / Beta-Casp domain / Zn-dependent metallo-hydrolase, RNA specificity domain / Zn-dependent metallo-hydrolase RNA specificity domain / Metallo-beta-lactamase superfamily / Metallo-beta-lactamase / Ribonuclease Z/Hydroxyacylglutathione hydrolase-like / Armadillo-like helical / Armadillo-type fold
Similarity search - Domain/homology
Integrator complex subunit 9 / Integrator complex subunit 11 / Integrator complex subunit 4
Similarity search - Component
Biological speciesDrosophila melanogaster (fruit fly)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.74 Å
AuthorsLin M / Tong L
Funding support United States, 3 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM134539 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM118093 United States
Cancer Prevention and Research Institute of Texas (CPRIT)RP170593 United States
CitationJournal: Nat Commun / Year: 2022
Title: Inositol hexakisphosphate is required for Integrator function.
Authors: Min-Han Lin / Madeline K Jensen / Nathan D Elrod / Kai-Lieh Huang / Kevin A Welle / Eric J Wagner / Liang Tong /
Abstract: Integrator is a multi-subunit protein complex associated with RNA polymerase II (Pol II), with critical roles in noncoding RNA 3'-end processing and transcription attenuation of a broad collection of ...Integrator is a multi-subunit protein complex associated with RNA polymerase II (Pol II), with critical roles in noncoding RNA 3'-end processing and transcription attenuation of a broad collection of mRNAs. IntS11 is the endonuclease for RNA cleavage, as a part of the IntS4-IntS9-IntS11 Integrator cleavage module (ICM). Here we report a cryo-EM structure of the Drosophila ICM, at 2.74 Å resolution, revealing stable association of an inositol hexakisphosphate (IP) molecule. The IP binding site is located in a highly electropositive pocket at an interface among all three subunits of ICM, 55 Å away from the IntS11 active site and generally conserved in other ICMs. We also confirmed IP association with the same site in human ICM. IP binding is not detected in ICM samples harboring mutations in this binding site. Such mutations or disruption of IP biosynthesis significantly reduced Integrator function in snRNA 3'-end processing and mRNA transcription attenuation. Our structural and functional studies reveal that IP is required for Integrator function in Drosophila, humans, and likely other organisms.
History
DepositionOct 27, 2021-
Header (metadata) releaseOct 12, 2022-
Map releaseOct 12, 2022-
UpdateJun 4, 2025-
Current statusJun 4, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_25214.png

Downloads & links

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Map

FileDownload / File: emd_25214.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.08 Å/pix.
x 256 pix.
= 277.248 Å		1.08 Å/pix.
x 256 pix.
= 277.248 Å		1.08 Å/pix.
x 256 pix.
= 277.248 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.083 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.028
Minimum - Maximum-0.14074597 - 0.26390722
Average (Standard dev.)-0.00006955377 (±0.005399295)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 277.248 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : Integrator cleavage module with inositol hexakisphosphate

EntireName: Integrator cleavage module with inositol hexakisphosphate
Components
  • Complex: Integrator cleavage module with inositol hexakisphosphate
    • Protein or peptide: Integrator complex subunit 4
    • Protein or peptide: Integrator complex subunit 11
    • Protein or peptide: Integrator complex subunit 9
  • Ligand: ZINC ION
  • Ligand: INOSITOL HEXAKISPHOSPHATE

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Supramolecule #1: Integrator cleavage module with inositol hexakisphosphate

SupramoleculeName: Integrator cleavage module with inositol hexakisphosphate
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Drosophila melanogaster (fruit fly)

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Macromolecule #1: Integrator complex subunit 4

MacromoleculeName: Integrator complex subunit 4 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Drosophila melanogaster (fruit fly)
Molecular weightTheoretical: 114.728875 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MHHHHHHGSG MALAIKKRVG TYVETVDGSP PVKKLRLQTL AADAKGGKSG KVGNVERKLT ALNQLDAYVG NLPAGALVLP TGTPVASTG APSTGVIGNP PAAATGAPPM TAANSRELLE LLVKITDEIS YEDVEMGELK EVASKIFQLY QLQERDSDTS I RVKLLELL ...String:
MHHHHHHGSG MALAIKKRVG TYVETVDGSP PVKKLRLQTL AADAKGGKSG KVGNVERKLT ALNQLDAYVG NLPAGALVLP TGTPVASTG APSTGVIGNP PAAATGAPPM TAANSRELLE LLVKITDEIS YEDVEMGELK EVASKIFQLY QLQERDSDTS I RVKLLELL SGLGCECATE QALTMIIDYF IFLLRKEVSQ KVLAQGMMCL FRIGERRKHM LPISYKTQVA HLAKEQLRSG SA HTQKNAM LVIGRFATKM EGERHYVWKL AFYIDSQDSS VRAQALHALL TLGERGSQLP AVLYKRAVEA MKDDYECVRK EAL QLVFML GNRHPDYILP SDRQQEELRM IDAAFSKVCE ALCDLSLQIR VLAAELLGGM TAVSREFLHQ TLDKKLMSNL RRKR TAHER GARLVASGEW SSGKRWADDA PQEHLDAQSI SIIASGACGA LIHGLEDEFL EVRTAAVASM CKLALSRPDF AVTSL DFLV DMFNDEIEDV RLKAIYSLTA IAKHIVLRED QLEIMLGSLE DYSVDVREGL HLMLGACRVS TQTCLLMVVQ KLLDVL AKY PQDRNSTYAC MRKIGQKHPH LVMAVAVHLL YVHPFFETPE RDVEDPAYLC VLILVFNAAE HLVPIISLLP TATHRHY AY LRDSMPNLVP QLPIEGASSA SATHRIDSAM HQAGSSAEYL QMILSHIEEI FTMTDERLEL LQTAQSNLQR LGSIDAGM Y GTSNFLETFL AAQIQIEQMQ RCASTQRSRV PLKESLAALI RNCLKLQHTF SGLNYGDILQ VKQLRLRACA LHLVLVVRD RSQSALGPCQ MLLQTAGDIS EFIKANTKDE EEKPPVVETD MPMKESVSRD AQPDSFTRQL LIKLDGISDP KPGRVFREIL PLVQQAPPL ALPPANDKIR RCVANILEPC PLQSQDNVIK VTAGLIAAVP FVAEIDNLLE SQKADMRIKI KYPDQHMHTV V PKQSDFKP IMTEQGEHKT NVRLRTTILL SHSVWTESSL VEIQLCLAVR PGSELELCKP AKVLFAPKPV RRGI

UniProtKB: Integrator complex subunit 4

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Macromolecule #2: Integrator complex subunit 11

MacromoleculeName: Integrator complex subunit 11 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
EC number: Hydrolases; Acting on ester bonds; Endoribonucleases producing 3'-phosphomonoesters
Source (natural)Organism: Drosophila melanogaster (fruit fly)
Molecular weightTheoretical: 67.683922 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MPDIKITPLG AGQDVGRSCL LLSMGGKNIM LDCGMHMGYN DERRFPDFSY IVPEGPITSH IDCVIISHFH LDHCGALPYM SEIVGYTGP IYMTHPTKAI APILLEDMRK VAVERKGESN FFTTQMIKDC MKKVIPVTLH QSMMVDTDLE IKAYYAGHVL G AAMFWIKV ...String:
MPDIKITPLG AGQDVGRSCL LLSMGGKNIM LDCGMHMGYN DERRFPDFSY IVPEGPITSH IDCVIISHFH LDHCGALPYM SEIVGYTGP IYMTHPTKAI APILLEDMRK VAVERKGESN FFTTQMIKDC MKKVIPVTLH QSMMVDTDLE IKAYYAGHVL G AAMFWIKV GSQSVVYTGD YNMTPDRHLG AAWIDKCRPD LLISESTYAT TIRDSKRCRE RDFLKKVHEC VAKGGKVLIP VF ALGRAQE LCILLETYWE RMNLKYPIYF ALGLTEKANT YYKMFITWTN QKIRKTFVHR NMFDFKHIKP FDKAYIDNPG AMV VFATPG MLHAGLSLQI FKKWAPNENN MVIMPGYCVQ GTVGNKILGG AKKVEFENRQ VVEVKMAVEY MSFSAHADAK GIMQ LIQNC EPKNVMLVHG EAGKMKFLRS KIKDEFNLET YMPANGETCV ISTPVKIPVD ASVSLLKAEA RSYNAQPPDP KRRRL IHGV LVMKDNRIML QNLTDALKEI GINRHVMRFT SKVKMDDSGP VIRTSERLKT LLEEKLAGWT VTMQENGSIA IESVEV KVE EDEKDPKQKN ILISWTNQDE DIGAYILNVL QNMC

UniProtKB: Integrator complex subunit 11

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Macromolecule #3: Integrator complex subunit 9

MacromoleculeName: Integrator complex subunit 9 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Drosophila melanogaster (fruit fly)
Molecular weightTheoretical: 73.351531 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MRLYCLSGDL AKPCYIITFK GLRIMLDCGL TEQTVLNFLP LPFVQSLKWS NLPNFVPSRD HDPQMDGELK DCCGRVFVDS TPEFNLPMD KMLDFSEVDV ILISNYLNML ALPYITENTG FKGKVYATEP TLQIGRFFLE ELVDYIEVSP KACTARLWKE K LHLLPSPL ...String:
MRLYCLSGDL AKPCYIITFK GLRIMLDCGL TEQTVLNFLP LPFVQSLKWS NLPNFVPSRD HDPQMDGELK DCCGRVFVDS TPEFNLPMD KMLDFSEVDV ILISNYLNML ALPYITENTG FKGKVYATEP TLQIGRFFLE ELVDYIEVSP KACTARLWKE K LHLLPSPL SEAFRAKKWR TIFSLKDVQG SLSKVTIMGY DEKLDILGAF IATPVSSGYC LGSSNWVLST AHEKICYVSG SS TLTTHPR PINQSALKHA DVLIMTGLTQ APTVNPDTKL GELCMNVALT IRNNGSALIP CYPSGVVYDL FECLTQNLEN AGL NNVPMF FISPVADSSL AYSNILAEWL SSAKQNKVYL PDDPFPHAFY LRNNKLKHYN HVFSEGFSKD FRQPCVVFCG HPSL RFGDA VHFIEMWGNN PNNSIIFTEP DFPYLQVLAP FQPLAMKAFY CPIDTSLNYQ QANKLIKELK PNVLVIPEAY TKPHP SAPN LFIEQPDKKI ITFKCGEIIR LPLKRKLDRI YITSELAQKI SPKEVAAGVT FSTLTGVLQV KDKVHCIQPC ADSVKD ETI SSNSAPTKED VLKNVKYEYG SIDVDAVMKK LAQDGFSNIK LDRTGGALTL NLVNEDTVIK FEDNETHIIC GGKPTTR LK LRDTIMKCLQ SF

UniProtKB: Integrator complex subunit 9

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Macromolecule #4: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 4 / Number of copies: 2 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #5: INOSITOL HEXAKISPHOSPHATE

MacromoleculeName: INOSITOL HEXAKISPHOSPHATE / type: ligand / ID: 5 / Number of copies: 1 / Formula: IHP
Molecular weightTheoretical: 660.035 Da
Chemical component information

ChemComp-IHP:
INOSITOL HEXAKISPHOSPHATE

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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: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number real images: 4395 / Average electron dose: 51.35 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm
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: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.74 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 620438
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: RANDOM ASSIGNMENT

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