4W9J

pVHL:EloB:EloC in complex with (2S,4R)-1-((S)-2-((S)-2-acetamido-4-methylpentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (ligand 13)

Summary for 4W9J

• Entry DOI: 10.2210/pdb4w9j/pdb
• Descriptor: Transcription elongation factor B polypeptide 2, Transcription elongation factor B polypeptide 1, Von Hippel-Lindau disease tumor suppressor, ... (5 entities in total)
• Functional Keywords: protein complex, ubiquitin ligase, hypoxia inducible factor, transcription
• 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: 169292.08

Authors

Gadd, M.S.,Galdeano, C.,van Molle, I.,Ciulli, A. (deposition date: 2014-08-27, release date: 2014-09-10, Last modification date: 2024-10-09)

Primary citation

Galdeano, C.,Gadd, M.S.,Soares, P.,Scaffidi, S.,Van Molle, I.,Birced, I.,Hewitt, S.,Dias, D.M.,Ciulli, A.
Structure-Guided Design and Optimization of Small Molecules Targeting the Protein-Protein Interaction between the von Hippel-Lindau (VHL) E3 Ubiquitin Ligase and the Hypoxia Inducible Factor (HIF) Alpha Subunit with in Vitro Nanomolar Affinities.
J.Med.Chem., 57:8657-8663, 2014

PubMed Abstract: E3 ubiquitin ligases are attractive targets in the ubiquitin-proteasome system, however, the development of small-molecule ligands has been rewarded with limited success. The von Hippel-Lindau protein (pVHL) is the substrate recognition subunit of the VHL E3 ligase that targets HIF-1α for degradation. We recently reported inhibitors of the pVHL:HIF-1α interaction, however they exhibited moderate potency. Herein, we report the design and optimization, guided by X-ray crystal structures, of a ligand series with nanomolar binding affinities.

PubMed: 25166285
DOI: 10.1021/jm5011258

Experimental method

X-RAY DIFFRACTION (2.2 Å)