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- EMDB-70123: ADAM17 Prodomain-Metalloproteinase Domains bound to MEDI3622 Fab -

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Basic information

Entry
Database: EMDB / ID: EMD-70123
TitleADAM17 Prodomain-Metalloproteinase Domains bound to MEDI3622 Fab
Map dataADAM17 Pro Cat bound to MEDI3622 Fab
Sample
  • Complex: Human ADAM17 Pro-Metalloprotease Bound to MEDI3622 Fab
    • Protein or peptide: Disintegrin and metalloproteinase domain-containing protein 17
    • Protein or peptide: MEDI3622 Fab Light Chain
    • Protein or peptide: MEDI3622 Fab Heavy Chain
  • Ligand: ZINC ION
KeywordsInhibitor / Complex / Sheddase / IMMUNE SYSTEM
Function / homologyDomain of unknown function DUF3850 / Domain of unknown function (DUF3850) / ASCH / ASCH domain / PUA-like superfamily / DUF3850 domain-containing protein
Function and homology information
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.5 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_70123.png

Downloads & links

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Map

FileDownload / File: emd_70123.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationADAM17 Pro Cat bound to MEDI3622 Fab
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.69 Å/pix.
x 360 pix.
= 248.4 Å		0.69 Å/pix.
x 360 pix.
= 248.4 Å		0.69 Å/pix.
x 360 pix.
= 248.4 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.69 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.102
Minimum - Maximum-0.4941514 - 0.75670356
Average (Standard dev.)-0.00017157766 (±0.015216723)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 248.4 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: ADAM17 Pro Cat bound to MEDI3622 Fab Half Map B

Fileemd_70123_half_map_1.map
AnnotationADAM17 Pro Cat bound to MEDI3622 Fab Half Map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: ADAM17 Pro Cat bound to MEDI3622 Fab Half Map A

Fileemd_70123_half_map_2.map
AnnotationADAM17 Pro Cat bound to MEDI3622 Fab Half Map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Human ADAM17 Pro-Metalloprotease Bound to MEDI3622 Fab

EntireName: Human ADAM17 Pro-Metalloprotease Bound to MEDI3622 Fab
Components
  • Complex: Human ADAM17 Pro-Metalloprotease Bound to MEDI3622 Fab
    • Protein or peptide: Disintegrin and metalloproteinase domain-containing protein 17
    • Protein or peptide: MEDI3622 Fab Light Chain
    • Protein or peptide: MEDI3622 Fab Heavy Chain
  • Ligand: ZINC ION

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Supramolecule #1: Human ADAM17 Pro-Metalloprotease Bound to MEDI3622 Fab

SupramoleculeName: Human ADAM17 Pro-Metalloprotease Bound to MEDI3622 Fab
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 100 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 / Details: Human ADAM17 Prodomain and Metalloprotease Domains / Number of copies: 1 / Enantiomer: LEVO / EC number: ec: 3.4.24.86
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 55.16298 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MRQSLLFLTS VVPFVLAPRP PDDPGFGPHQ RLEKLDSLLS DYDILSLSNI QQHSVRKADL QTSTHVETLL TFSALKRHFK LYLTSSTER FSQNFKVVVV DGKNESEYTV KWQDFFTGHV VGEPDSRVLA HIRDDDVIIR INTDGAEYNI EPLWRFVNDT K DKRMLVYK ...String:
MRQSLLFLTS VVPFVLAPRP PDDPGFGPHQ RLEKLDSLLS DYDILSLSNI QQHSVRKADL QTSTHVETLL TFSALKRHFK LYLTSSTER FSQNFKVVVV DGKNESEYTV KWQDFFTGHV VGEPDSRVLA HIRDDDVIIR INTDGAEYNI EPLWRFVNDT K DKRMLVYK SEDIKQVSRL QSPKVCGYLK VDNEELLPKG LVDREPPEEL VHAVKARADP DPMKNTCKLL VVADHRFYRY MG RGEESTT TNYLIELIDR VDDIYRNTSW DNAGFKGYGI QIEQIRILKS PQEVKPGEKH YNMAKSYPNE EKDAWDVKML LEQ FSFDIA EEASKVCLAH LFTYQDFDMG TLGLAYVGSP RANSHGGVCP KAYYSPVGKK NIYLNSGLTS TKNYGKTILT KEAD LVTTH ELGHNFGAEH DPDGLAECAP NEDQGGKYVM YPIAVSGDHE NNKMFSNCSK QSIYKTIESK AQECFQERSN KVHHH HHH

UniProtKB: DUF3850 domain-containing protein

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Macromolecule #2: MEDI3622 Fab Light Chain

MacromoleculeName: MEDI3622 Fab Light Chain / type: protein_or_peptide / ID: 2 / Details: Light Chain MEDI3622 Fab / 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 #3: MEDI3622 Fab Heavy Chain

MacromoleculeName: MEDI3622 Fab Heavy Chain / type: protein_or_peptide / ID: 3 / Details: MEDI3622 Fab Heavy Chain / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.65857 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 PKSCL

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Macromolecule #4: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 4 / 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

Concentration0.25 mg/mL
BufferpH: 8
Component:
ConcentrationFormulaName
20.0 mMC8H18N2O4SHEPES
150.0 mMNaClSodium Chloride
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.4 µm

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 98475
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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