A Newfound Cancer-Activating Mutation Reshapes the Energy Landscape of Estrogen-Binding Domain
mediaposted on 12.08.2014 by Wei Huang, Krishnakumar M. Ravikumar, Sichun Yang
Media is any form of research output that is recorded and played. This is most commonly video, but can be audio or 3D representations.
The ligand-binding domain (LBD) of an estrogen receptor undergoes a large conformational switching from an inactive to active state in response to hormone stimuli. Very recently, a novel D538G mutant has been identified to be active in advanced breast cancer tumors. Here, we ask if molecular simulations can provide insight on its mechanistic impact on the receptor’s activation status. It has been challenging for ab initio modeling to identify two distinct conformations of a single amino acid sequence as large as that of the LBD. Using a coarse-grained (CG) model, we are able to correctly reproduce this LBD conformational switching. Furthermore, we found that the D538G mutation reshapes the energy landscape by stabilizing both active and inactive conformations, but preferring the active by 1.5 kcal/mol. This observation is consistent with the concept of a mutation-shifting landscape and provides a structural explanation for the oncogenic D538G mutation at the detailed conformational level.