5NW1
pVHL:EloB:EloC in complex with (2S,4R)-1-((S)-2-(cyclobutanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (ligand 18)
Summary for 5NW1
| Entry DOI | 10.2210/pdb5nw1/pdb |
| Descriptor | Elongin-B, Elongin-C, Von Hippel-Lindau disease tumor suppressor, ... (5 entities in total) |
| Functional Keywords | protein complex, ubiquitin ligase, hypoxia inducible factor, ligase |
| Biological source | Homo sapiens (Human) More |
| Cellular location | Nucleus : Q15370 Q15369 Isoform 1: Cytoplasm. Isoform 3: Cytoplasm: P40337 |
| Total number of polymer chains | 12 |
| Total formula weight | 168999.70 |
| Authors | Gadd, M.S.,Soares, P.,Ciulli, A. (deposition date: 2017-05-04, release date: 2017-09-20, Last modification date: 2024-10-23) |
| Primary citation | 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 Cited by 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: 28853884DOI: 10.1021/acs.jmedchem.7b00675 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.1 Å) |
Structure validation
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