8PKW

Kelch domain of KEAP1 in complex with a ortho-dimethylbenzene linked cyclic peptide 5 (ortho-WRCDPETaEC).

8PKW の概要

• エントリーDOI: 10.2210/pdb8pkw/pdb
• 分子名称: Kelch-like ECH-associated protein 1, CP5, SULFATE ION, ... (9 entities in total)
• 機能のキーワード: peptide inhibitor, inhibitor complex, cyclic peptide, ubiquitin ligase, nrf2, protein binding
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 71307.05

構造登録者

Braun, M.B.,Bischof, L.,Hartmann, M.D. (登録日: 2023-06-27, 公開日: 2023-11-15, 最終更新日: 2024-10-16)

主引用文献

Fonseca Lopez, F.,Miao, J.,Damjanovic, J.,Bischof, L.,Braun, M.B.,Ling, Y.,Hartmann, M.D.,Lin, Y.S.,Kritzer, J.A.
Computational Prediction of Cyclic Peptide Structural Ensembles and Application to the Design of Keap1 Binders.
J.Chem.Inf.Model., 63:6925-6937, 2023

PubMed Abstract: The Nrf2 transcription factor is a master regulator of the cellular response to oxidative stress, and Keap1 is its primary negative regulator. Activating Nrf2 by inhibiting the Nrf2-Keap1 protein-protein interaction has shown promise for treating cancer and inflammatory diseases. A loop derived from Nrf2 has been shown to inhibit Keap1 selectively, especially when cyclized, but there are no reliable design methods for predicting an optimal macrocyclization strategy. In this work, we employed all-atom, explicit-solvent molecular dynamics simulations with enhanced sampling methods to predict the relative degree of preorganization for a series of peptides cyclized with a set of bis-thioether "staples". We then correlated these predictions to experimentally measured binding affinities for Keap1 and crystal structures of the cyclic peptides bound to Keap1. This work showcases a computational method for designing cyclic peptides by simulating and comparing their entire solution-phase ensembles, providing key insights into designing cyclic peptides as selective inhibitors of protein-protein interactions.

PubMed: 37917529
DOI: 10.1021/acs.jcim.3c01337

実験手法

X-RAY DIFFRACTION (1.54 Å)