5NW0

pVHL:EloB:EloC in complex with (2S,4R)-1-((S)-2-(1-acetamidocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (ligand 17)

5NW0 の概要

• エントリーDOI: 10.2210/pdb5nw0/pdb
• 分子名称: Elongin-B, Elongin-C, Von Hippel-Lindau disease tumor suppressor, ... (5 entities in total)
• 機能のキーワード: protein complex, ubiquitin ligase, hypoxia inducible factor, ligase
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Nucleus : Q15370 Q15369; Isoform 1: Cytoplasm. Isoform 3: Cytoplasm: P40337
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 169171.80

構造登録者

Gadd, M.S.,Soares, P.,Ciulli, A. (登録日: 2017-05-04, 公開日: 2017-09-20, 最終更新日: 2024-10-23)

主引用文献

Soares, P.,Gadd, M.S.,Frost, J.,Galdeano, C.,Ellis, L.,Epemolu, O.,Rocha, S.,Read, K.D.,Ciulli, A.
Group-Based Optimization of Potent and Cell-Active Inhibitors of the von Hippel-Lindau (VHL) E3 Ubiquitin Ligase: Structure-Activity Relationships Leading to the Chemical Probe (2S,4R)-1-((S)-2-(1-Cyanocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (VH298).
J. Med. Chem., 61:599-618, 2018

PubMed Abstract: The von Hippel-Lindau tumor suppressor protein is the substrate binding subunit of the VHL E3 ubiquitin ligase, which targets hydroxylated α subunit of hypoxia inducible factors (HIFs) for ubiquitination and subsequent proteasomal degradation. VHL is a potential target for treating anemia and ischemic diseases, motivating the development of inhibitors of the VHL:HIF-α protein-protein interaction. Additionally, bifunctional proteolysis targeting chimeras (PROTACs) containing a VHL ligand can hijack the E3 ligase activity to induce degradation of target proteins. We report the structure-guided design and group-based optimization of a series of VHL inhibitors with low nanomolar potencies and improved cellular permeability. Structure-activity relationships led to the discovery of potent inhibitors 10 and chemical probe VH298, with dissociation constants <100 nM, which induced marked HIF-1α intracellular stabilization. Our study provides new chemical tools to probe the VHL-HIF pathways and new VHL ligands for next-generation PROTACs.

PubMed: 28853884
DOI: 10.1021/acs.jmedchem.7b00675

実験手法

X-RAY DIFFRACTION (2.3 Å)