8VHG

Structure of the BMAL1/HIF2A heterodimer in Complex with DNA

Summary for 8VHG

• Entry DOI: 10.2210/pdb8vhg/pdb
• EMDB information: 43237
• Descriptor: Endothelial PAS domain-containing protein 1, Basic helix-loop-helix ARNT-like protein 1, Reverse strand DNA containing HRE motif, ... (4 entities in total)
• Functional Keywords: transcriptional factors, heterodimer, dna recognition, circadian-dependent cardioprotection, transcription-dna complex, transcription/dna
• Biological source: Mus musculus (house mouse); More
• Total number of polymer chains: 4
• Total formula weight: 107364.89

Authors

Li, T.,Tsai, K.L. (deposition date: 2024-01-01, release date: 2025-02-12, Last modification date: 2025-06-04)

Primary citation

Ruan, W.,Li, T.,Bang, I.H.,Lee, J.,Deng, W.,Ma, X.,Luo, C.,Du, F.,Yoo, S.H.,Kim, B.,Li, J.,Yuan, X.,Figarella, K.,An, Y.A.,Wang, Y.Y.,Liang, Y.,DeBerge, M.,Zhang, D.,Zhou, Z.,Wang, Y.,Gorham, J.M.,Seidman, J.G.,Seidman, C.E.,Aranki, S.F.,Nair, R.,Li, L.,Narula, J.,Zhao, Z.,Gorfe, A.A.,Muehlschlegel, J.D.,Tsai, K.L.,Eltzschig, H.K.
BMAL1-HIF2A heterodimer modulates circadian variations of myocardial injury.
Nature, 641:1017-1028, 2025

PubMed Abstract: Acute myocardial infarction is a leading cause of morbidity and mortality worldwide. Clinical studies have shown that the severity of cardiac injury after myocardial infarction exhibits a circadian pattern, with larger infarcts and poorer outcomes in patients experiencing morning-onset events. However, the molecular mechanisms underlying these diurnal variations remain unclear. Here we show that the core circadian transcription factor BMAL1 regulates circadian-dependent myocardial injury by forming a transcriptionally active heterodimer with a non-canonical partner-hypoxia-inducible factor 2 alpha (HIF2A)-in a diurnal manner. To substantiate this finding, we determined the cryo-EM structure of the BMAL1-HIF2A-DNA complex, revealing structural rearrangements within BMAL1 that enable cross-talk between circadian rhythms and hypoxia signalling. BMAL1 modulates the circadian hypoxic response by enhancing the transcriptional activity of HIF2A and stabilizing the HIF2A protein. We further identified amphiregulin (AREG) as a rhythmic target of the BMAL1-HIF2A complex, critical for regulating daytime variations of myocardial injury. Pharmacologically targeting the BMAL1-HIF2A-AREG pathway provides cardioprotection, with maximum efficacy when aligned with the pathway's circadian phase. These findings identify a mechanism governing circadian variations of myocardial injury and highlight the therapeutic potential of clock-based pharmacological interventions for treating ischaemic heart disease.

PubMed: 40269168
DOI: 10.1038/s41586-025-08898-z

Experimental method

ELECTRON MICROSCOPY (3.6 Å)