Molecular modeling on HIF-2α–ARNT dimer destabilization caused by R171A and/or V192D mutations in HIF-2α |
| |
Affiliation: | 1. Department of Physics, University of Alabama in Huntsville, Huntsville, AL 35899, United States;2. Department of Chemistry, University of Alabama in Huntsville, Huntsville, AL 35899, United States;3. Materials Science Graduate Program, University of Alabama in Huntsville, Huntsville, AL 35899, United States;4. Sentinel Inc., 4733 Commercial Drive, Huntsville, AL 35816, United States |
| |
Abstract: | 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. |
| |
Keywords: | Molecular dynamics simulation Mutation HIF-2α ARNT |
本文献已被 ScienceDirect 等数据库收录! |
|