Abstract
Animals respond to chronic hypoxia by increasing the levels of a transcription factor known as the hypoxia‐inducible factor (HIF). HIF upregulates multiple genes, the products of which work to ameliorate the effects of limited oxygen at cellular and systemic levels. Hypoxia sensing by the HIF system involves hydroxylase‐catalysed post‐translational modifications of the HIF α‐subunits, which 1) signal for degradation of HIF‐α and 2) limit binding of HIF to transcriptional coactivator proteins. Because the hypoxic response is relevant to multiple disease states, therapeutic manipulation of the HIF‐mediated response has considerable medicinal potential. In addition to modulation of catalysis by the HIF hydroxylases, the HIF system manifests other possibilities for therapeutic intervention involving protein–protein and protein–nucleic acid interactions. Recent advances in our understanding of the structural biology and biochemistry of the HIF system are facilitating medicinal chemistry efforts. Herein we give an overview of the HIF system, focusing on structural knowledge of protein–protein interactions and how this might be used to modulate the hypoxic response for therapeutic benefit.
Highlights
The chronic response to hypoxia in humans and other animals is substantially mediated by the a,b-heterodimeric hypoxia-inducible factor (HIF) transcription factor.[1]
We give an overview of the HIF system, focusing on structural knowledge of protein–protein interactions and how this might be used to modulate the hypoxic response for therapeutic benefit
Considerable progress has been made towards developing chemically useful inhibitors of the sets of enzymes underlying HIF-a hydroxylation, that is, the PHDs, and in demonstrating that disrupting the interactions between prolyl hydroxylated HIF-a and pVHL is a tractable target for small molecules
Summary
The chronic response to hypoxia (limited oxygen availability) in humans and other animals is substantially mediated by the a,b-heterodimeric hypoxia-inducible factor (HIF) transcription factor.[1]. Together with transcriptional coactivator proteins, HIF promotes the context-dependent expression of multiple genes that work to counteract the effects of hypoxia at a cellular, and subsequently, systemic level.[2] there are other mechanisms of hypoxic adaptation, including those acting on a shorter time-scale than the HIF system, the extent of the effects of the HIF system has led HIF to be characterised as a master regulator of the hypoxic response. The regulation of protein–protein interactions by oxygen-dependent post-translational modifications is central to the hypoxia-sensing capacity of the HIF system. Other protein–protein and protein–nucleic acid interactions play central roles in the HIF system and offer therapeutic possibilities. The purpose of this review is to give an overview of the HIF system, focusing on knowledge of the oligomeric interactions involved, and outlining how this knowledge might be exploited for therapeutic benefit
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