4IN4

Crystal structure of cpd 15 bound to Keap1 Kelch domain

Summary for 4IN4

• Entry DOI: 10.2210/pdb4in4/pdb
• Related: 4IQK
• Descriptor: Kelch-like ECH-associated protein 1, PHOSPHATE ION, 2-({5-[(2,4-dimethylphenyl)sulfonyl]-6-oxo-1,6-dihydropyrimidin-2-yl}sulfanyl)-N-[2-(trifluoromethyl)phenyl]acetamide, ... (4 entities in total)
• Functional Keywords: transcription
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: Q14145
• Total number of polymer chains: 3
• Total formula weight: 101780.53

Authors

Silvian, L.,Marcotte, D. (deposition date: 2013-01-03, release date: 2013-05-15, Last modification date: 2023-09-20)

Primary citation

Marcotte, D.,Zeng, W.,Hus, J.C.,McKenzie, A.,Hession, C.,Jin, P.,Bergeron, C.,Lugovskoy, A.,Enyedy, I.,Cuervo, H.,Wang, D.,Atmanene, C.,Roecklin, D.,Vecchi, M.,Vivat, V.,Kraemer, J.,Winkler, D.,Hong, V.,Chao, J.,Lukashev, M.,Silvian, L.
Small molecules inhibit the interaction of Nrf2 and the Keap1 Kelch domain through a non-covalent mechanism.
Bioorg.Med.Chem., 21:4011-4019, 2013

PubMed Abstract: Keap1 binds to the Nrf2 transcription factor to promote its degradation, resulting in the loss of gene products that protect against oxidative stress. While cell-active small molecules have been identified that modify cysteines in Keap1 and effect the Nrf2 dependent pathway, few act through a non-covalent mechanism. We have identified and characterized several small molecule compounds that specifically bind to the Keap1 Kelch-DC domain as measured by NMR, native mass spectrometry and X-ray crystallography. One compound upregulates Nrf2 response genes measured by a luciferase cell reporter assay. The non-covalent inhibition strategy presents a reasonable course of action to avoid toxic side-effects due to non-specific cysteine modification.

PubMed: 23647822
DOI: 10.1016/j.bmc.2013.04.019

Experimental method

X-RAY DIFFRACTION (2.59 Å)