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- PDB-9o54: ADAM17 Prodomain-Metalloproteinase Domains bound to MEDI3622 Fab -

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Basic information

Entry
Database: PDB / ID: 9o54
TitleADAM17 Prodomain-Metalloproteinase Domains bound to MEDI3622 Fab
Components
  • Disintegrin and metalloproteinase domain-containing protein 17
  • MEDI3622 Fab Heavy Chain
  • MEDI3622 Fab Light Chain
KeywordsIMMUNE SYSTEM / Inhibitor / Complex / Sheddase
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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsSlone, C.E. / Maciag, J.J.
Funding support United States, 1items
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, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 25, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Disintegrin and metalloproteinase domain-containing protein 17
C: MEDI3622 Fab Light Chain
D: MEDI3622 Fab Heavy Chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)102,2124
Polymers102,1463
Non-polymers651
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Disintegrin and metalloproteinase domain-containing protein 17 / ADAM 17 / Snake venom-like protease / TNF-alpha convertase / TNF-alpha-converting enzyme


Mass: 55162.980 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Human ADAM17 Prodomain and Metalloprotease Domains / Source: (gene. exp.) Homo sapiens (human) / Gene: ADAM17, CSVP, TACE / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P78536, EC: 3.4.24.86
#2: Antibody MEDI3622 Fab Light Chain


Mass: 23324.887 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Light Chain MEDI3622 Fab / Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): Expi293 / Production host: Homo sapiens (human)
#3: Antibody MEDI3622 Fab Heavy Chain


Mass: 23658.570 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: MEDI3622 Fab Heavy Chain / Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Human ADAM17 Pro-Metalloprotease Bound to MEDI3622 Fab
Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightValue: 0.1 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 8
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMHEPESC8H18N2O4S1
2150 mMSodium ChlorideNaCl1
SpecimenConc.: 0.25 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: SPOT SCAN
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 400 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.20.1_4487 / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 98475 / Symmetry type: POINT
RefinementHighest resolution: 3.5 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0036574
ELECTRON MICROSCOPYf_angle_d0.6248909
ELECTRON MICROSCOPYf_dihedral_angle_d4.31895
ELECTRON MICROSCOPYf_chiral_restr0.042982
ELECTRON MICROSCOPYf_plane_restr0.0071150

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