UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Molecular basis for the disruption of Keap1–Nrf2 interaction via Hinge & Latch mechanism

Horie, Y; Suzuki, T; Inoue, J; Iso, T; Wells, G; Moore, TW; Mizushima, T; ... Yamamoto, M; + view all (2021) Molecular basis for the disruption of Keap1–Nrf2 interaction via Hinge & Latch mechanism. Communications Biology , 4 (1) 10.1038/s42003-021-02100-6. Green open access

[img]
Preview
Text
CommBiol2021 Keap1-Nrf2 Hinge-Latch Mechanism.pdf - Published version

Download (2MB) | Preview

Abstract

The Keap1-Nrf2 system is central for mammalian cytoprotection against various stresses and a drug target for disease prevention and treatment. One model for the molecular mechanisms leading to Nrf2 activation is the Hinge-Latch model, where the DLGex-binding motif of Nrf2 dissociates from Keap1 as a latch, while the ETGE motif remains attached to Keap1 as a hinge. To overcome the technical difficulties in examining the binding status of the two motifs during protein-protein interaction (PPI) simultaneously, we utilized NMR spectroscopy titration experiments. Our results revealed that latch dissociation is triggered by low-molecular-weight Keap1-Nrf2 PPI inhibitors and occurs during p62-mediated Nrf2 activation, but not by electrophilic Nrf2 inducers. This study demonstrates that Keap1 utilizes a unique Hinge-Latch mechanism for Nrf2 activation upon challenge by non-electrophilic PPI-inhibiting stimuli, and provides critical insight for the pharmacological development of next-generation Nrf2 activators targeting the Keap1-Nrf2 PPI.

Type: Article
Title: Molecular basis for the disruption of Keap1–Nrf2 interaction via Hinge & Latch mechanism
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s42003-021-02100-6
Publisher version: https://doi.org/10.1038/s42003-021-02100-6
Language: English
Additional information: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Keywords: Molecular biology; Solution-state NMR
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharma and Bio Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/10127982
Downloads since deposit
8Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item