This study describes the long-awaited crystal structures for hypoxia-inducible factor (HIF) heterodimers, including complexes bound to small molecules and DNA. HIFs are transcription factors that coordinate cellular adaptation to low oxygen stress and are potential targets for cancer therapeutics. The mouse HIF–ARNT heterodimer is shown to have an architecture that is distinct from the bHLH-PAS-containing circadian clock component CLOCK–BMAL1. HIF-α mutations linked to cancer can be mapped to important structural regions, and the structures will provide future reference for small molecule drug discovery efforts.
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