6SP4

KEAP1 IN COMPLEX WITH COMPOUND 23

6SP4 の概要

• エントリーDOI: 10.2210/pdb6sp4/pdb
• 分子名称: Kelch-like ECH-associated protein 1, (1~{S},2~{R})-2-[[(1~{S})-1-[[1,3-bis(oxidanylidene)isoindol-2-yl]methyl]-5-(2-hydroxyethyloxy)-3,4-dihydro-1~{H}-isoquinolin-2-yl]carbonyl]cyclobutane-1-carboxamide (3 entities in total)
• 機能のキーワード: nrf2, keap1, protein-protein interactions, huntingtons disease, tetrahydroisoquinoline, protein binding
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 194575.69

構造登録者

Ontoria, J.M.,Biancofiore, I.,Fezzardi, P.,Torrente de Haro, E.,Colarusso, S.,Bianchi, E.,Andreini, M.,Patsilinakos, A.,Summa, V.,Pacifici, R.,Munoz-Sanjuan, I.,Park, L.,Bresciani, A.,Dominguez, C.,Toledo-Sherman, L.,Harper, S. (登録日: 2019-08-30, 公開日: 2020-06-03, 最終更新日: 2024-11-13)

主引用文献

Ontoria, J.M.,Biancofiore, I.,Fezzardi, P.,Ferrigno, F.,Torrente, E.,Colarusso, S.,Bianchi, E.,Andreini, M.,Patsilinakos, A.,Kempf, G.,Augustin, M.,Steinbacher, S.,Summa, V.,Pacifici, R.,Munoz-Sanjuan, I.,Park, L.,Bresciani, A.,Dominguez, C.,Sherman, L.T.,Harper, S.
Combined Peptide and Small-Molecule Approach toward Nonacidic THIQ Inhibitors of the KEAP1/NRF2 Interaction.
Acs Med.Chem.Lett., 11:740-746, 2020

PubMed Abstract: The NRF2-ARE pathway is an intrinsic mechanism of defense against oxidative stress. Inhibition of the interaction between NRF2 and its main negative regulator KEAP1 is an attractive strategy toward neuroprotective agents. We report here the identification of nonacidic tetrahydroisoquinolines (THIQs) that inhibit the KEAP1/NRF2 protein-protein interaction. Peptide SAR at one residue is utilized as a tool to probe structural changes within a specific pocket of the KEAP1 binding site. We used structural information from peptide screening at the P2 pocket, noncovalent small-molecules inhibitors, and the outcome from an explorative SAR at position 5 of THIQs to identify a series of neutral THIQ analogs that bind to KEAP1 in the low micromolar range. These analogs establish new H-bond interactions at the P3 and P2 pockets allowing the replacement of the carboxylic acid functionality by a neutral primary carboxamide. X-ray crystallographic studies reveal the novel binding mode of these molecules to KEAP1.

PubMed: 32435379
DOI: 10.1021/acsmedchemlett.9b00594

実験手法

X-RAY DIFFRACTION (2.59 Å)