6T7Z

KEAP1 IN COMPLEX WITH COMPOUND 44

Summary for 6T7Z

• Entry DOI: 10.2210/pdb6t7z/pdb
• Descriptor: Kelch-like ECH-associated protein 1, ACE-CYS-ASA-4FB-GLU-THR-GLY-GLU-CYS-NH2, ACETATE ION, ... (4 entities in total)
• Functional Keywords: keap1, ubiquitinylation, inrf2, kiaa0132, klhl19, proteros biostructures gmbh, transcription
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 33082.87

Authors

Colarusso, S. (deposition date: 2019-10-23, release date: 2020-09-09, Last modification date: 2024-11-06)

Primary citation

Colarusso, S.,De Simone, D.,Frattarelli, T.,Andreini, M.,Cerretani, M.,Missineo, A.,Moretti, D.,Tambone, S.,Kempf, G.,Augustin, M.,Steinbacher, S.,Munoz-Sanjuan, I.,Park, L.,Summa, V.,Tomei, L.,Bresciani, A.,Dominguez, C.,Toledo-Sherman, L.,Bianchi, E.
Optimization of linear and cyclic peptide inhibitors of KEAP1-NRF2 protein-protein interaction.
Bioorg.Med.Chem., 28:115738-115738, 2020

PubMed Abstract: Inhibition of KEAP1-NRF2 protein-protein interaction is considered a promising strategy to selectively and effectively activate NRF2, a transcription factor which is involved in several pathologies such as Huntington's disease (HD). A library of linear peptides based on the NRF2-binding motifs was generated on the nonapeptide lead Ac-LDEETGEFL-NH spanning residues 76-84 of the Neh2 domain of NRF2 with the aim to replace E78, E79 and E82 with non-acidic amino acids. A deeper understanding of the features and accessibility of the T80 subpocket was also targeted by structure-based design. Approaches to improve cell permeability were investigated using both different classes of cyclic peptides and conjugation to cell-penetrating peptides. This insight will guide future design of macrocycles, peptido-mimetics and, most importantly, small neutral brain-penetrating molecules to evaluate whether NRF2 activators have utility in HD.

PubMed: 33065433
DOI: 10.1016/j.bmc.2020.115738

Experimental method

X-RAY DIFFRACTION (2 Å)