5LLI

pVHL:EloB:EloC in complex with VH298

Summary for 5LLI

• Entry DOI: 10.2210/pdb5lli/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, chemical probe, 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: 169043.63

Authors

Gadd, M.S.,Soares, P.,Galdeano, C.,Ciulli, A. (deposition date: 2016-07-27, release date: 2016-11-09, Last modification date: 2024-10-09)

Primary citation

Frost, J.,Galdeano, C.,Soares, P.,Gadd, M.S.,Grzes, K.M.,Ellis, L.,Epemolu, O.,Shimamura, S.,Bantscheff, M.,Grandi, P.,Read, K.D.,Cantrell, D.A.,Rocha, S.,Ciulli, A.
Potent and selective chemical probe of hypoxic signalling downstream of HIF-alpha hydroxylation via VHL inhibition.
Nat Commun, 7:13312-13312, 2016

PubMed Abstract: Chemical strategies to using small molecules to stimulate hypoxia inducible factors (HIFs) activity and trigger a hypoxic response under normoxic conditions, such as iron chelators and inhibitors of prolyl hydroxylase domain (PHD) enzymes, have broad-spectrum activities and off-target effects. Here we disclose VH298, a potent VHL inhibitor that stabilizes HIF-α and elicits a hypoxic response via a different mechanism, that is the blockade of the VHL:HIF-α protein-protein interaction downstream of HIF-α hydroxylation by PHD enzymes. We show that VH298 engages with high affinity and specificity with VHL as its only major cellular target, leading to selective on-target accumulation of hydroxylated HIF-α in a concentration- and time-dependent fashion in different cell lines, with subsequent upregulation of HIF-target genes at both mRNA and protein levels. VH298 represents a high-quality chemical probe of the HIF signalling cascade and an attractive starting point to the development of potential new therapeutics targeting hypoxia signalling.

PubMed: 27811928
DOI: 10.1038/ncomms13312

Experimental method

X-RAY DIFFRACTION (2.4 Å)