Fig. 5: A possible common mechanism in ligand binding shared by HIF-2α.

a The residues of Fα and Gβ with reduced deuteration levels are mapped on the crystal structure in blue, and the R308 in Gβ of HIF-2α forms a hydrogen bond with the A/B loop of ARNT. Hydrogen bonds are shown in red dotted lines. b Two routes previously proposed for ligands to enter or leave the HIF-2α PAS-B pocket are indicated by black arrows, and enlarged views of two routes are shown on the left and right sides, respectively. The possible new entry route of ligands into HIF-2α, corresponding to that of OEA into HIF-3α, is shown by a green arrow, with the residues surrounding the entrance also colored green. M252 and Y281 are shown in magenta in the apo structure, and blue in co-crystal structures. M252 and Y281 were flipped outwards (as shown by dotted arrows) by antagonist PT2385 and agonist M1001, respectively. The PDB codes of HIF-2α-ARNT-PT2385 and HIF-2α-ARNT-M1001 are 6E3S and 6E3U. c Cα RMSF plots for HIF-2α in a monomeric system. The highly flexible regions including modelled linkers (black) and loop-Aβ (magenta) are highlighted. d The conformational change of the loop-Aβ region in snapshot structures extracted from the trajectories of HIF-2α during the MD stimulations.