7O7B

Solution NMR Structure of the Neh1 Domain of Human Nuclear factor erythroid 2-related factor 2 (NRF2)

Summary for 7O7B

• Entry DOI: 10.2210/pdb7o7b/pdb
• NMR Information: BMRB: 34617
• Descriptor: Isoform 3 of Nuclear factor erythroid 2-related factor 2 (1 entity in total)
• Functional Keywords: cap n collar (cnc), basic leucine zipper (bzip) transcription factor, antioxidant response, dna binding protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 9422.03

Authors

Brueschweiler, S. (deposition date: 2021-04-13, release date: 2021-09-29, Last modification date: 2024-06-19)

Primary citation

Bruschweiler, S.,Fuchs, J.E.,Bader, G.,McConnell, D.B.,Konrat, R.,Mayer, M.
A Step toward NRF2-DNA Interaction Inhibitors by Fragment-Based NMR Methods.
Chemmedchem, 16:3576-3587, 2021

PubMed Abstract: The NRF2 transcription factor is a key regulator in cellular oxidative stress response, and acts as a tumor suppressor. Aberrant activation of NRF2 has been implicated in promoting chemo-resistance, tumor growth, and metastasis by activating its downstream target genes. Hence, inhibition of NRF2 promises to be an attractive therapeutic strategy to suppress cell proliferation and enhance cell apoptosis in cancer. Direct targeting of NRF2 with small-molecules to discover protein-DNA interaction inhibitors is challenging as it is a largely intrinsically disordered protein. To discover molecules that bind to NRF2 at the DNA binding interface, we performed an NMR-based fragment screen against its DNA-binding domain. We discovered several weakly binding fragment hits that bind to a region overlapping with the DNA binding site. Using SAR by catalogue we developed an initial structure-activity relationship for the most interesting initial hit series. By combining NMR chemical shift perturbations and data-driven docking, binding poses which agreed with NMR information and the observed SAR were elucidated. The herein discovered NRF2 hits and proposed binding modes form the basis for future structure-based optimization campaigns on this important but to date 'undrugged' cancer driver.

PubMed: 34524728
DOI: 10.1002/cmdc.202100458

Experimental method

SOLUTION NMR