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- EMDB-70127: Zymogen ADAM17-iRhom2 complex bound by the MEDI3622 Fab -

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Entry
Database: EMDB / ID: EMD-70127
TitleZymogen ADAM17-iRhom2 complex bound by the MEDI3622 Fab
Map dataFull Map
Sample
  • Complex: Zymogen ADA17-iRhom2 complex bound by the MEDI3622 Fab
    • Protein or peptide: GFP-iRhom2 fusion protein
    • Protein or peptide: MEDI3622 Fab Light Chain
    • Protein or peptide: MEDI3622 Fab Heavy Chain
  • Protein or peptide: Disintegrin and metalloproteinase domain-containing protein 17
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CALCIUM ION
  • Ligand: ZINC ION
KeywordsInhibitor / Complex / Sheddase / IMMUNE SYSTEM
Function / homology
Function and homology information


ADAM 17 endopeptidase / regulation of mast cell apoptotic process / signal release / positive regulation of epidermal growth factor-activated receptor activity / metalloendopeptidase activity involved in amyloid precursor protein catabolic process / regulation of epidermal growth factor receptor signaling pathway / cellular response to high density lipoprotein particle stimulus / Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant / Notch receptor processing / interleukin-6 receptor binding ...ADAM 17 endopeptidase / regulation of mast cell apoptotic process / signal release / positive regulation of epidermal growth factor-activated receptor activity / metalloendopeptidase activity involved in amyloid precursor protein catabolic process / regulation of epidermal growth factor receptor signaling pathway / cellular response to high density lipoprotein particle stimulus / Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant / Notch receptor processing / interleukin-6 receptor binding / protein transporter activity / tumor necrosis factor binding / positive regulation of T cell chemotaxis / TNF signaling / positive regulation of leukocyte chemotaxis / Release of Hh-Np from the secreting cell / Regulated proteolysis of p75NTR / commissural neuron axon guidance / positive regulation of tumor necrosis factor-mediated signaling pathway / neutrophil mediated immunity / germinal center formation / Notch binding / wound healing, spreading of epidermal cells / positive regulation of vascular endothelial cell proliferation / negative regulation of cold-induced thermogenesis / CD163 mediating an anti-inflammatory response / positive regulation of epidermal growth factor receptor signaling pathway / cell adhesion mediated by integrin / regulation of protein secretion / Signaling by EGFR / growth factor binding / amyloid precursor protein catabolic process / cytokine binding / Collagen degradation / membrane protein ectodomain proteolysis / positive regulation of blood vessel endothelial cell migration / negative regulation of protein secretion / positive regulation of G1/S transition of mitotic cell cycle / Growth hormone receptor signaling / Nuclear signaling by ERBB4 / spleen development / positive regulation of chemokine production / Notch signaling pathway / Constitutive Signaling by NOTCH1 HD Domain Mutants / B cell differentiation / Activated NOTCH1 Transmits Signal to the Nucleus / bioluminescence / protein localization to plasma membrane / generation of precursor metabolites and energy / PDZ domain binding / phosphatidylinositol 3-kinase/protein kinase B signal transduction / cell motility / negative regulation of inflammatory response to antigenic stimulus / negative regulation of transforming growth factor beta receptor signaling pathway / protein processing / metalloendopeptidase activity / SH3 domain binding / Golgi lumen / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / epidermal growth factor receptor signaling pathway / metallopeptidase activity / positive regulation of tumor necrosis factor production / integrin binding / protein transport / peptidase activity / actin cytoskeleton / T cell differentiation in thymus / positive regulation of cell growth / endopeptidase activity / response to lipopolysaccharide / response to hypoxia / defense response to Gram-positive bacterium / cell adhesion / positive regulation of cell migration / apical plasma membrane / membrane raft / endoplasmic reticulum lumen / response to xenobiotic stimulus / Golgi membrane / positive regulation of cell population proliferation / endoplasmic reticulum membrane / cell surface / proteolysis / metal ion binding / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Rhomboid serine protease / : / Inactive rhomboid proteins 1/2, N-terminal / ADAM17, membrane-proximal domain / Membrane-proximal domain, switch, for ADAM17 / Metallo-peptidase family M12 / ADAM10/ADAM17 catalytic domain / : / Peptidase S54, rhomboid domain / Rhomboid domain ...Rhomboid serine protease / : / Inactive rhomboid proteins 1/2, N-terminal / ADAM17, membrane-proximal domain / Membrane-proximal domain, switch, for ADAM17 / Metallo-peptidase family M12 / ADAM10/ADAM17 catalytic domain / : / Peptidase S54, rhomboid domain / Rhomboid domain / Rhomboid-like superfamily / Disintegrin / Disintegrin domain profile. / Homologues of snake disintegrins / Disintegrin domain / Disintegrin domain superfamily / Peptidase M12B, ADAM/reprolysin / ADAM type metalloprotease domain profile. / Metallopeptidase, catalytic domain superfamily / Green fluorescent protein, GFP / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent protein / Neutral zinc metallopeptidases, zinc-binding region signature.
Similarity search - Domain/homology
Green fluorescent protein / Disintegrin and metalloproteinase domain-containing protein 17 / Inactive rhomboid protein 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.53 Å
AuthorsSlone CE / Maciag JJ
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM146830 United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2025
Title: Structural insights into the activation and inhibition of the ADAM17-iRhom2 complex.
Authors: Joseph J Maciag / Conner E Slone / Hala F Alnajjar / Maria F Rich / Bryce Guion / Igal Ifergan / Carl P Blobel / Tom C M Seegar /
Abstract: The endopeptidase activity of ADAM (a disintegrin and metalloproteinase)-17, the primary processor of several EGFR ligands and tumor necrosis factor-alpha (TNF-α), is essential for proper embryonic ...The endopeptidase activity of ADAM (a disintegrin and metalloproteinase)-17, the primary processor of several EGFR ligands and tumor necrosis factor-alpha (TNF-α), is essential for proper embryonic development and immune regulation. Dysregulated ADAM17 activity is prevalent in a wide array of human diseases, including cancer, chronic inflammation, and SARS-CoV-2 viral progression. Initially translated as an inactive zymogen, ADAM17 maturation and enzymatic function are tightly regulated by its obligate binding partners, the inactive rhomboid proteins (iRhom) -1 and -2. Here, we present the cryo-EM structure of the ADAM17 zymogen bound to iRhom2. Our findings elucidate the interactions within the ADAM17-iRhom2 complex, the inhibitory mechanisms of the therapeutic MEDI3622 antibody and ADAM17 prodomain, and the previously unknown role of a membrane-proximal cytoplasmic reentry loop of iRhom2 involved in the mechanism of activation. Importantly, we perform cellular assays to validate our structural findings and provide further insights into the functional implications of these interactions, paving the way for developing therapeutic strategies targeting this biomedically critical enzyme complex.
History
DepositionApr 9, 2025-
Header (metadata) releaseJun 25, 2025-
Map releaseJun 25, 2025-
UpdateJun 25, 2025-
Current statusJun 25, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_70127.png

Downloads & links

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Map

FileDownload / File: emd_70127.map.gz / Format: CCP4 / Size: 325 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationFull Map
Projections & slices

Image control

Size
Brightness
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AxesZ (Sec.)Y (Row.)X (Col.)
0.82 Å/pix.
x 440 pix.
= 361.68 Å		0.82 Å/pix.
x 440 pix.
= 361.68 Å		0.82 Å/pix.
x 440 pix.
= 361.68 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.822 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.102
Minimum - Maximum-0.30498308 - 0.5982725
Average (Standard dev.)0.00016250246 (±0.013599094)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions440440440
Spacing440440440
CellA=B=C: 361.68002 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half Map A

Fileemd_70127_half_map_1.map
AnnotationHalf Map A
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Half map: Half Map B

Fileemd_70127_half_map_2.map
AnnotationHalf Map B
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : Zymogen ADA17-iRhom2 complex bound by the MEDI3622 Fab

EntireName: Zymogen ADA17-iRhom2 complex bound by the MEDI3622 Fab
Components
  • Complex: Zymogen ADA17-iRhom2 complex bound by the MEDI3622 Fab
    • Protein or peptide: GFP-iRhom2 fusion protein
    • Protein or peptide: MEDI3622 Fab Light Chain
    • Protein or peptide: MEDI3622 Fab Heavy Chain
  • Protein or peptide: Disintegrin and metalloproteinase domain-containing protein 17
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CALCIUM ION
  • Ligand: ZINC ION

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Supramolecule #1: Zymogen ADA17-iRhom2 complex bound by the MEDI3622 Fab

SupramoleculeName: Zymogen ADA17-iRhom2 complex bound by the MEDI3622 Fab
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #2-#4
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 230 KDa

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Macromolecule #1: Disintegrin and metalloproteinase domain-containing protein 17

MacromoleculeName: Disintegrin and metalloproteinase domain-containing protein 17
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: ADAM 17 endopeptidase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 91.328742 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: PHQRLEKLDS LLSDYDILSL SNIQQHSVRK RDLQTSTHVE TLLTFSALKR HFKLYLTSST ERFSQNFKVV VVDGKNESEY TVKWQDFFT GHVVGEPDSR VLAHIRDDDV IIRINTDGAE YNIEPLWRFV NDTKDKRMLV YKSEDIKNVS RLQSPKVCGY L KVDNEELL ...String:
PHQRLEKLDS LLSDYDILSL SNIQQHSVRK RDLQTSTHVE TLLTFSALKR HFKLYLTSST ERFSQNFKVV VVDGKNESEY TVKWQDFFT GHVVGEPDSR VLAHIRDDDV IIRINTDGAE YNIEPLWRFV NDTKDKRMLV YKSEDIKNVS RLQSPKVCGY L KVDNEELL PKGLVDREPP EELVHRVKRR ADPDPMKNTC KLLVVADHRF YRYMGRGEES TTTNYLIELI DRVDDIYRNT SW DNAGFKG YGIQIEQIRI LKSPQEVKPG EKHYNMAKSY PNEEKDAWDV KMLLEQFSFD IAEEASKVCL AHLFTYQDFD MGT LGLAYV GSPRANSHGG VCPKAYYSPV GKKNIYLNSG LTSTKNYGKT ILTKEADLVT THALGHNFGA EHDPDGLAEC APNE DQGGK YVMYPIAVSG DHENNKMFSN CSKQSIYKTI ESKAQECFQE RSNKVCGNSR VDEGEECDPG IMYLNNDTCC NSDCT LKEG VQCSDRNSPC CKNCQFETAQ KKCQEAINAT CKGVSYCTGN SSECPPPGNA EDDTVCLDLG KCKDGKCIPF CEREQQ LES CACNETDNSC KVCCRDLSGR CVPYVDAEQK NLFLRKGKPC TVGFCDMNGK CEKRVQDVIE RFWDFIDQLS INTFGKF LA DNIVGSVLVF SLIFWIPFSI LVHCVDKKLD KQYESLSLFH PSNVEMLSSM DSASVRIIKP FPAPQTPGRL QPAPVIPS A PAAPKLDHQR MDTIQEDPST DSHMDEDGFE KDPFPNSSTA AKSFEDLTDH PVTRSEKAAS FKLQRQNRVD SKETECEQK LISEEDL

UniProtKB: Disintegrin and metalloproteinase domain-containing protein 17

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Macromolecule #2: GFP-iRhom2 fusion protein

MacromoleculeName: GFP-iRhom2 fusion protein / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 84.277539 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MVSKGEELFT GVVPILVELD GDVNGHKFSV SGEGEGDATY GKLTLKLICT TGKLPVPWPT LVTTLGYGLQ CFARYPDHMK QHDFFKSAM PEGYVQERTI FFKDDGNYKT RAEVKFEGDT LVNRIELKGI DFKEDGNILG HKLEYNYNSH NVYITADKQK N GIKANFKI ...String:
MVSKGEELFT GVVPILVELD GDVNGHKFSV SGEGEGDATY GKLTLKLICT TGKLPVPWPT LVTTLGYGLQ CFARYPDHMK QHDFFKSAM PEGYVQERTI FFKDDGNYKT RAEVKFEGDT LVNRIELKGI DFKEDGNILG HKLEYNYNSH NVYITADKQK N GIKANFKI RHNIEDGGVQ LADHYQQNTP IGDGPVLLPD NHYLSYQSKL SKDPNEKRDH MVLLEFVTAA GITLGMDELY KD YKDDDKS GRKKRHYGLG VVGNWLNRSY RRSISSTVQR QLESFDSHRP YFTYWLTFVH VIITLLVICT YGIAPVGFAQ HVT TQLVLR NKGVYESVKY IQQENFWVGP SSIDLIHLGA KFSPCIRKDG QIEQLVLRER DLERDSGCCV QNDHSGCIQT QRKD CSETL ATFVKWQDDT GPPMDKSDLG QKRTSGAVCH QDPRTCEEPA SSGAHIWPDD ITKWPICTEQ ARSNHTGFLH MDCEI KGRP CCIGTKGSCE ITTREYCEFM HGYFHEEATL CSQVHCLDKV CGLLPFLNPE VPDQFYRLWL SLFLHAGVVH CLVSVV FQM TILRDLEKLA GWHRIAIIFI LSGITGNLAS AIFLPYRAEV GPAGSQFGLL ACLFVELFQS WPLLERPWKA FLNLSAI VL FLFICGLLPW IDNIAHIFGF LSGLLLAFAF LPYITFGTSD KYRKRALILV SLLAFAGLFA ALVLWLYIYP INWPWIEH L TCFPFTSRFC EKYELDQVLH

UniProtKB: Green fluorescent protein, Inactive rhomboid protein 2

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Macromolecule #3: MEDI3622 Fab Light Chain

MacromoleculeName: MEDI3622 Fab Light Chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.324887 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DIQMTQSPSS LSASVGDRVT ITCRSSQSIP SYLNWYQQKP GKAPKLLIYA ASRLQSGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQ QSYSTPLTFG GGTKVEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS ...String:
DIQMTQSPSS LSASVGDRVT ITCRSSQSIP SYLNWYQQKP GKAPKLLIYA ASRLQSGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQ QSYSTPLTFG GGTKVEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS KDSTYSLSST LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC

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Macromolecule #4: MEDI3622 Fab Heavy Chain

MacromoleculeName: MEDI3622 Fab Heavy Chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.44227 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EVQLLESGGG LVQPGGSLRL SCAASGFTFS SYPMNWVRQA PGKGLEWVSY ISPFGGMTDY ATSVKGRFTI SRDNSKNTLY LQMNSLRAE DTAVYYCARD AMRGAEVDYW GQGTLVTVSS ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS W NSGALTSG ...String:
EVQLLESGGG LVQPGGSLRL SCAASGFTFS SYPMNWVRQA PGKGLEWVSY ISPFGGMTDY ATSVKGRFTI SRDNSKNTLY LQMNSLRAE DTAVYYCARD AMRGAEVDYW GQGTLVTVSS ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS W NSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSSLGTQ TYICNVNHKP SNTKVDKRVE PKS

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Macromolecule #6: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 6 / Number of copies: 6 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #7: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 7 / Number of copies: 1 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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Macromolecule #8: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 8 / Number of copies: 1 / 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

Concentration5.3 mg/mL
BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 58.3 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.4 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: 3.53 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 46753
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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