HIFα–ARNT heterodimers exhibit distinct domain interactions and small-molecule binding pockets.

  • Major finding: HIFα–ARNT heterodimers exhibit distinct domain interactions and small-molecule binding pockets.

  • Clinical relevance: Cancer-related mutations in HIF1A and HIF2A map to domain interfaces, pockets, and DNA binding sites.

  • Impact: The small-molecule binding pockets may enable selective therapeutic targeting of HIF1α and HIF2α.

Hypoxia-inducible factor α (HIFα) proteins heterodimerize with aryl hydrocarbon receptor nuclear translocator (ARNT, also known as HIF1β) to form active transcription factors that control the molecular response to low oxygen. HIFs regulate genes involved in a variety of adaptive cellular processes, including metabolism, angiogenesis, and erythropoiesis, and dysregulation of HIF signaling has been implicated in tumorigenesis, supporting the development of small-molecule HIF inhibitors. To provide a better understanding of HIF function and drug-binding capabilities, Wu and colleagues solved the crystal structure of the basic helix–loop–helix (bHLH), PAS-A, and PAS-B domains of HIF2α–ARNT heterodimers. This analysis revealed an integrated quarternary architecture distinct from the domain interactions observed in heterodimers of other bHLH–PAS proteins, with asymmetrical interactions between the domains of HIF2α and ARNT proteins and formation of a single DNA-reading head at one end of the heterodimer. Mutagenesis analysis revealed that these domain–domain interactions were required to stabilize the complex. Structural analysis of HIF2α–ARNT bound to synthetic small molecules identified five potential binding pockets within the PAS domains, which may facilitate selective small-molecule binding to either HIF1α or HIF2α. In addition, comparison of the structures of HIFα–ARNT heterodimers in complex with DNA containing the core hypoxia response element highlighted identical interactions of the bHLH domains of HIF1α and HIF2α with DNA and cooperation between the PAS-A domain and the bHLH domains in DNA recognition. Furthermore, cancer-associated mutations in HIF1A and HIF2A were found to map to pocket regions, domain interfaces, or sites important for DNA binding. Together, these findings demonstrate the unique domain arrangements of HIFα–ARNT heterodimers and suggest that the identified pockets may facilitate therapeutic targeting of HIF1α and HIF2α.

Wu D, Potluri N, Lu J, Kim Y, Rastinejad F. Structural integration in hypoxia-inducible factors. Nature 2015;524:303–8.

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