Molecular modeling on HIF-2α-ARNT dimer destabilization caused by R171A and/or V192D mutations in HIF-2α.

Oxygen homeostasis in normal and tumor cells is mediated by hypoxia-inducible factors (HIFs), which are active as heterodimer complexes, such as HIF-2α-aryl hydrocarbon receptor nuclear translocator (ARNT) and HIF-1α-ARNT. A series of mutations on the interfaces between HIF-2α and ARNT and on the domain-domain interface within HIF-2α has been reported to exert varying effects on HIF-2α-ARNT dimerization. In the present study, molecular dynamic simulations were conducted to evaluate HIF-2α mutations, namely R171A, V192D, and R171A/V192D, which are not involved in the interaction with ARNT but impede HIF-2α-ARNT dimerization. Our results indicate that these mutations induct local conformation leading to a shortened (by V192D) or widened (by R171A and R171A/V192D) Y91-E346 separation distance, where E346 and Y91 are located on the HIF-2α and interact with ARNT according to electrostatic and geometrical shape complementarity, respectively.