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TitleStructural insights into the activation and inhibition of the ADAM17-iRhom2 complex.
Journal, issue, pagesProc Natl Acad Sci U S A, Vol. 122, Issue 24, Page e2500732122, Year 2025
Publish dateJun 17, 2025
AuthorsJoseph J Maciag / Conner E Slone / Hala F Alnajjar / Maria F Rich / Bryce Guion / Igal Ifergan / Carl P Blobel / Tom C M Seegar /
PubMed AbstractThe 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.
External linksProc Natl Acad Sci U S A / PubMed:40512800 / PubMed Central
MethodsEM (single particle)
Resolution3.5 - 3.53 Å
Structure data

70123

9o54

EMDB-70123, PDB-9o54:
ADAM17 Prodomain-Metalloproteinase Domains bound to MEDI3622 Fab
Method: EM (single particle) / Resolution: 3.5 Å

70127

9o58

EMDB-70127, PDB-9o58:
Zymogen ADAM17-iRhom2 complex bound by the MEDI3622 Fab
Method: EM (single particle) / Resolution: 3.53 Å

Chemicals

ChemComp-ZN:
Unknown entry

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

ChemComp-CA:
Unknown entry

Source
  • homo sapiens (human)
  • aequorea victoria (jellyfish)
KeywordsIMMUNE SYSTEM / Inhibitor / Complex / Sheddase

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