4N1B

STRUCTURE OF KEAP1 KELCH DOMAIN WITH(1S,2R)-2-[(1S)-1-[(1-oxo-2,3-dihydro-1H-isoindol-2-Yl)methyl]-1,2,3,4-tetrahydroisoquinoline-2-Carbonyl]cyclohexane-1-carboxylic acid

Summary for 4N1B

• Entry DOI: 10.2210/pdb4n1b/pdb
• Related: 4L7B 4L7C 4L7D
• Descriptor: Kelch-like ECH-associated protein 1, (1S,2R)-2-{[(1S)-1-[(1-oxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}cyclohexanecarboxylic acid, ACETATE ION, ... (4 entities in total)
• Functional Keywords: replacement soaking, stress sensor, small molecular binding, kelch domain, kelch repeat motif, beta-propeller, nrf2, protein-small molecule complex, cytosol, transcription-inhibitor complex, transcription/inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: Q14145
• Total number of polymer chains: 3
• Total formula weight: 100445.03

Authors

Smith, M.A.,Duclos, S.,Beaumont, E.,Kwong, J.,Brooks, M.,Barker, J.,Jnoff, E.,Brookfield, F.,Courade, J.P.,Barker, O.,Fryatt, T.,Albrecht, C.,Bromidge, S. (deposition date: 2013-10-03, release date: 2014-02-19, Last modification date: 2024-10-16)

Primary citation

Jnoff, E.,Albrecht, C.,Barker, J.J.,Barker, O.,Beaumont, E.,Bromidge, S.,Brookfield, F.,Brooks, M.,Bubert, C.,Ceska, T.,Corden, V.,Dawson, G.,Duclos, S.,Fryatt, T.,Genicot, C.,Jigorel, E.,Kwong, J.,Maghames, R.,Mushi, I.,Pike, R.,Sands, Z.A.,Smith, M.A.,Stimson, C.C.,Courade, J.P.
Binding Mode and Structure-Activity Relationships around Direct Inhibitors of the Nrf2-Keap1 Complex.
Chemmedchem, 9:699-705, 2014

PubMed Abstract: An X-ray crystal structure of Kelch-like ECH-associated protein (Keap1) co-crystallised with (1S,2R)-2-[(1S)-1-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-2-carbonyl]cyclohexane-1-carboxylic acid (compound (S,R,S)-1 a) was obtained. This X-ray crystal structure provides breakthrough experimental evidence for the true binding mode of the hit compound (S,R,S)-1 a, as the ligand orientation was found to differ from that of the initial docking model, which was available at the start of the project. Crystallographic elucidation of this binding mode helped to focus and drive the drug design process more effectively and efficiently.

PubMed: 24504667
DOI: 10.1002/cmdc.201300525

Experimental method

X-RAY DIFFRACTION (2.55 Å)