Asset Details
Do you wish to reserve the book?
Ion channel inhibition by targeted recruitment of NEDD4-2 with divalent nanobodies
Hey, we have placed the reservation for you!
By the way, why not check out events that you can attend while you pick your title.
Oops! Something went wrong.
Looks like we were not able to place the reservation. Kindly try again later.
Are you sure you want to remove the book from the shelf?
Ion channel inhibition by targeted recruitment of NEDD4-2 with divalent nanobodies
Do you wish to request the book?
Ion channel inhibition by targeted recruitment of NEDD4-2 with divalent nanobodies
Please be aware that the book you have requested cannot be checked out. If you would like to checkout this book, you can reserve another copy
We have requested the book for you!
Your request is successful and it will be processed during the Library working hours. Please check the status of your request in My Requests.
Oops! Something went wrong.
Looks like we were not able to place your request. Kindly try again later.
Journal Article
Ion channel inhibition by targeted recruitment of NEDD4-2 with divalent nanobodies
2025
Overview
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.
Researchers develop a new way to selectively remove ion channel proteins by recruiting the body’s own NEDD4-2 enzyme using custom nanobodies, offering a precise and general strategy for future drug development.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 42/109
/ 82/58
/ 9/74
/ Animals
/ Calcium channels (voltage-gated)
/ Epithelial Sodium Channels - genetics
/ Epithelial Sodium Channels - metabolism
/ Humanities and Social Sciences
/ Humans
/ Ion Channels - antagonists & inhibitors
/ KCNQ1 Potassium Channel - antagonists & inhibitors
/ KCNQ1 Potassium Channel - genetics
/ KCNQ1 Potassium Channel - metabolism
/ Nedd4 Ubiquitin Protein Ligases - genetics
/ Nedd4 Ubiquitin Protein Ligases - metabolism
/ Potassium channels (voltage-gated)
/ Proteins
/ Science
/ Single-Domain Antibodies - metabolism
