1. Division of Structural Biology, Henry Wellcome Building of Genomic Medicine, Roosevelt Drive, Oxford OX3 7BN, UK
2. Cellular Physiology Group, Henry Wellcome Building of Genomic Medicine, Roosevelt Drive, Oxford OX3 7BN, UK
3. Oxford Centre for Molecular Sciences and Dyson Perrins Laboratory, South Parks Road, Oxford OX1 3QY, UK
4. These authors contributed equally to this work
5. Present address: Division of PNAC, MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK

Correspondence to: E. Yvonne Jones¹ Correspondence and requests for materials should be addressed to E.Y.J. (e-mail: Email: yvonne@strubi.ox.ac.uk) or P.J.R. (e-mail: Email: peter.ratcliffe@ndm.ox.ac.uk). Coordinates and structure factors have been deposited in the Protein Data Bank under accession codes 1LQB and RCSB016181.

Abstract

Hypoxia-inducible factor-1 (HIF-1) is a transcriptional complex that controls cellular and systemic homeostatic responses to oxygen availability¹. HIF-1 is the oxygen-regulated subunit of HIF-1, an heterodimeric complex¹. HIF-1 is stable in hypoxia, but in the presence of oxygen it is targeted for proteasomal degradation by the ubiquitination complex pVHL, the protein of the von Hippel–Lindau (VHL) tumour suppressor gene and a component of an E3 ubiquitin ligase complex^{2, 3}. Capture of HIF-1 by pVHL is regulated by hydroxylation of specific prolyl residues in two functionally independent regions of HIF-1^{4, 5, 6, 7}. The crystal structure of a hydroxylated HIF-1 peptide bound to VCB (pVHL, elongins C and B) and solution binding assays reveal a single, conserved hydroxyproline-binding pocket in pVHL. Optimized hydrogen bonding to the buried hydroxyprolyl group confers precise discrimination between hydroxylated and unmodified prolyl residues. This mechanism provides a new focus for development of therapeutic agents to modulate cellular responses to hypoxia.