4w9i
From Proteopedia
pVHL:EloB:EloC in complex with (2S,4R)-1-((2S,4R)-1-acetyl-4-hydroxypyrrolidine-2-carbonyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (ligand 10)
Structural highlights
FunctionELOB_HUMAN SIII, also known as elongin, is a general transcription elongation factor that increases the RNA polymerase II transcription elongation past template-encoded arresting sites. Subunit A is transcriptionally active and its transcription activity is strongly enhanced by binding to the dimeric complex of the SIII regulatory subunits B and C (elongin BC complex).[1] [2] The elongin BC complex seems to be involved as an adapter protein in the proteasomal degradation of target proteins via different E3 ubiquitin ligase complexes, including the von Hippel-Lindau ubiquitination complex CBC(VHL). By binding to BC-box motifs it seems to link target recruitment subunits, like VHL and members of the SOCS box family, to Cullin/RBX1 modules that activate E2 ubiquitination enzymes.[3] [4] Publication Abstract from PubMedE3 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-1alpha for degradation. We recently reported inhibitors of the pVHL:HIF-1alpha interaction that however exhibited moderate potency. Herein, we report the design and optimization, guided by X-ray crystal structures, of a ligand series with nanomolar binding affinities. 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.,Galdeano C, Gadd MS, Soares P, Scaffidi S, Van Molle I, Birced I, Hewitt S, Dias DM, Ciulli A J Med Chem. 2014 Aug 28. PMID:25166285[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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