Extended Data Fig. 10: Structural analysis of the BMAL1/HIF2A/DNA complex.

a, Four domain interfaces (I to IV) between BMAL1 and HIF2A. Each of these is indicated by a dashed ellipse. b, Zoom-in views of the interfaces (I to IV) between HIF2A and BMAL1. c, Comparison of the DNA-binding by two bHLH domains in HIF1B/HIF2A (left, PDB ID 4ZPK), BMAL1/HIF2A (middle), and BMAL1/CLOCK (right, PDB ID 4H10). The DNA contacted by the bHLH domains is highlighted in yellow. The PAS domains are omitted for clarity. d, Structural comparison of BMAL1/HIF2A with BMAL1/CLOCK (PDB ID: 4F3L) and HIF1B/HIF2A (PDB ID: 4ZPK). Upper: Structural comparison of BMAL1/HIF2A with BMAL1/CLOCK and HIF1B/HIF2A by aligning bHLH domains (highlighted in blue dashed frames). For clarity, DNA was omitted. Middle: Structure of BMAL1/CLOCK with its BMAL1 PAS-A domain (dashed circle) aligned to that of BMAL1/HIF2A. Lower: Structural comparison of the PAS-B dimers of BMAL1/HIF2A, BMAL1/CLOCK and HIF1B/HIF2A. The conserved residues in the HI loop and their interacting residues are shown. e, Structural comparison of BMAL1/HIF2A and BMAL1/CLOCK by aligning the PAS-A domains of BMAL1. BMAL1 is coloured in red in the BMAL1/HIF2A complex and in grey in the BMAL1/CLOCK complex. f, BMAL1 undergoes structural rearrangements upon binding with various partners. Superimposing the BMAL1/HIF2A and BMAL1/CLOCK complexes by aligning their bHLH domains reveals that BMAL1 (red) undergoes a substantial conformational change, with the two PAS domains bending in nearly opposite directions. BMAL1 exhibits a compact overall architecture when bound with CLOCK (green) and a distinctly separated conformation when interacting with HIF2A (purple).