9z5q

HECT domain of NEDD4-2 complex with a targeted nanobody, nb.C11

spinqualitylabelsall models 9z5q, resolution 3.06Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9z5q is a 2 chain structure with sequence from Homo sapiens and Lama glama. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.06Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function NED4L_HUMAN E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Inhibits TGF-beta signaling by triggering SMAD2 and TGFBR1 ubiquitination and proteasome-dependent degradation. Promotes ubiquitination and internalization of various plasma membrane channels such as ENaC, Nav1.2, Nav1.3, Nav1.5, Nav1.7, Nav1.8, Kv1.3, EAAT1 or CLC5. Promotes ubiquitination and degradation of SGK1 and TNK2. Publication Abstract from PubMed Targeted 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 (Ca(V)2.2; 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. Ion channel inhibition by targeted recruitment of NEDD4-2 with divalent nanobodies.,Darko-Boateng A, Afriyie E, Morgenstern TJ, Shanmugam SK, Zou X, Laloudakis YD, Choudhury P, Desai M, Kass RS, Vallese F, Clarke OB, Colecraft HM Nat Commun. 2025 Dec 6. doi: 10.1038/s41467-025-67068-x. PMID:41353348 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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