8pkv | pdb_00008pkv

Kelch domain of KEAP1 in complex with a ortho-dimethylbenzene linked cyclic peptide 4 (ortho-WRCDEETGEC)

spinqualitylabelsall models 8pkv, resolution 1.55Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8pkv is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.55Å Ligands: ACE, CL, EDO, GOL, NA, NH2, SO4, ZK2 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function KEAP1_HUMAN Publication Abstract from PubMed 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. Computational Prediction of Cyclic Peptide Structural Ensembles and Application to the Design of Keap1 Binders.,Fonseca Lopez F, Miao J, Damjanovic J, Bischof L, Braun MB, Ling Y, Hartmann MD, Lin YS, Kritzer JA J Chem Inf Model. 2023 Nov 13;63(21):6925-6937. doi: 10.1021/acs.jcim.3c01337. , Epub 2023 Nov 2. PMID:37917529 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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