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TitleIon channel inhibition by targeted recruitment of NEDD4-2 with divalent nanobodies.
Journal, issue, pagesNat Commun, Vol. 17, Issue 1, Page 378, Year 2025
Publish dateDec 6, 2025
AuthorsArden Darko-Boateng / Emmanuel Afriyie / Travis J Morgenstern / Sri Karthika Shanmugam / Xinle Zou / Yianni D Laloudakis / Papiya Choudhury / Meera Desai / Robert S Kass / Francesca Vallese / Oliver B Clarke / Henry M Colecraft /
PubMed AbstractTargeted protein degradation/downregulation (TPD/TPDR) is a disruptive paradigm for developing therapeutics. <2% of ~600 E3 ligases have been exploited for this modality, and efficacy for multi-subunit ion channels has not been demonstrated. NEDD4-2 E3 ligase regulates myriad ion channels, but its utility for TPD/TPDR is uncertain due to complex regulatory mechanisms. Here, we identify a nanobody that binds NEDD4-2 HECT domain without disrupting catalysis sites as revealed by cryo-electron microscopy and in vitro ubiquitination assays. Recruiting NEDD4-2 to diverse ion channels (Ca2.2; KCNQ1; and epithelial Na channel, ENaC, with a Liddle syndrome mutation) using divalent nanobodies (DiVas) strongly suppresses their surface density and function. Global proteomics indicates DiVa recruitment of endogenous NEDD4-2 to KCNQ1-YFP yields dramatically lower off-target effects compared to NEDD4-2 overexpression. The results establish utility of NEDD4-2 recruitment for TPD/TPDR, validate ion channels as susceptible to this modality, and introduce a general method to generate ion channel inhibitors.
External linksNat Commun / PubMed:41353348 / PubMed Central
MethodsEM (single particle)
Resolution3.06 Å
Structure data

73821

9z5q

EMDB-73821, PDB-9z5q:
HECT domain of NEDD4-2 complex with a targeted nanobody, nb.C11
Method: EM (single particle) / Resolution: 3.06 Å

Source
  • homo sapiens (human)
  • lama glama (llama)
KeywordsLIGASE / Ubiquitin / targeted protein degradation / E3 ligase / Nanobody

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