5FNQ
Structure of the Keap1 Kelch domain in complex with a small molecule inhibitor.
Summary for 5FNQ
Entry DOI | 10.2210/pdb5fnq/pdb |
Related | 5FNR 5FNS 5FNT 5FNU |
Descriptor | KELCH-LIKE ECH-ASSOCIATED PROTEIN 1, 3-(4-CHLOROPHENYL)PROPANOIC ACID (3 entities in total) |
Functional Keywords | transcription, keap1, nrf2, oxidative stress |
Biological source | MUS MUSCULUS (HOUSE MOUSE) |
Cellular location | Cytoplasm : Q9Z2X8 |
Total number of polymer chains | 1 |
Total formula weight | 33546.92 |
Authors | Davies, T.G.,Wixted, W.E.,Coyle, J.E.,Griffiths-Jones, C.,Hearn, K.,McMenamin, R.,Norton, D.,Rich, S.J.,Richardson, C.,Saxty, G.,Willems, H.M.G.,Woolford, A.J.,Cottom, J.E.,Kou, J.,Yonchuk, J.G.,Feldser, H.G.,Sanchez, Y.,Foley, J.P.,Bolognese, B.J.,Logan, G.,Podolin, P.L.,Yan, H.,Callahan, J.F.,Heightman, T.D.,Kerns, J.K. (deposition date: 2015-11-16, release date: 2016-04-13, Last modification date: 2024-01-10) |
Primary citation | Davies, T.G.,Wixted, W.E.,Coyle, J.E.,Griffiths-Jones, C.,Hearn, K.,Mcmenamin, R.L.,Norton, D.,Rich, S.J.,Richardson, C.,Saxty, G.,Willems, H.M.G.,Woolford, A.J.,Cottom, J.E.,Kou, J.,Yonchuk, J.G.,Feldser, H.G.,Sanchez, Y.,Foley, J.P.,Bolognese, B.J.,Logan, G.A.,Podolin, P.L.,Yan, H.,Callahan, J.F.,Heightman, T.D.,Kerns, J.K. Mono-Acidic Inhibitors of the Kelch-Like Ech-Associated Protein 1 : Nuclear Factor Erythroid 2-Related Factor 2 (Keap1:Nrf2) Protein-Protein Interaction with High Cell Potency Identified by Fragment-Based Discovery. J.Med.Chem., 59:3991-, 2016 Cited by PubMed Abstract: KEAP1 is the key regulator of the NRF2-mediated cytoprotective response, and increasingly recognized as a target for diseases involving oxidative stress. Pharmacological intervention has focused on molecules that decrease NRF2-ubiquitination through covalent modification of KEAP1 cysteine residues, but such electrophilic compounds lack selectivity and may be associated with off-target toxicity. We report here the first use of a fragment-based approach to directly target the KEAP1 Kelch-NRF2 interaction. X-ray crystallographic screening identified three distinct "hot-spots" for fragment binding within the NRF2 binding pocket of KEAP1, allowing progression of a weak fragment hit to molecules with nanomolar affinity for KEAP1 while maintaining drug-like properties. This work resulted in a promising lead compound which exhibits tight and selective binding to KEAP1, and activates the NRF2 antioxidant response in cellular and in vivo models, thereby providing a high quality chemical probe to explore the therapeutic potential of disrupting the KEAP1-NRF2 interaction. PubMed: 27031670DOI: 10.1021/ACS.JMEDCHEM.6B00228 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (1.91 Å) |
Structure validation
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