A Newfound Cancer-Activating Mutation Reshapes the Energy Landscape of Estrogen-Binding Domain

2014 ◽  
Vol 10 (8) ◽  
pp. 2897-2900 ◽  
Author(s):  
Wei Huang ◽  
Krishnakumar M. Ravikumar ◽  
Sichun Yang
Keyword(s):  
Energy Landscape ◽  
Binding Domain ◽  
Activating Mutation ◽  
Estrogen Binding

scholarly journals Identification of Amino Acids in the Hormone Binding Domain of the Human Estrogen Receptor Important in Estrogen Binding

1996 ◽  
Vol 271 (33) ◽  
pp. 20053-20059 ◽  
Author(s):  
Kirk Ekena ◽  
Karen E. Weis ◽  
John A. Katzenellenbogen ◽  
Benita S. Katzenellenbogen
Keyword(s):  
Amino Acids ◽  
Estrogen Receptor ◽  
Binding Domain ◽  
Hormone Binding ◽  
Human Estrogen Receptor ◽  
Estrogen Binding ◽  
Hormone Binding Domain

scholarly journals Dissociation pathways of the p53 DNA binding domain from DNA and critical roles of key residues elucidated by dPaCS-MD/MSM

2021 ◽  
Author(s):  
Mohamed Sobeh ◽  
Akio kitao
Keyword(s):  
Free Energy ◽  
Dna Binding ◽  
Energy Landscape ◽  
Minor Groove ◽  
Binding Domain ◽  
Free Energy Landscape ◽  
Dna Binding Domain ◽  
Major Groove ◽  
Dna Duplex ◽  
Key Residues

The dissociation process of the DNA binding domain of p53 (p53-DBD) from a DNA duplex that contains the consensus sequence, which is the specific target of p53-DBD, was investigated by a combination of dissociation parallel cascade selection molecular dynamics (dPaCS-MD) and the Markov state model (MSM). Based on an all-atom model including explicit solvent, we first simulated the p53-DBD dissociation processes by 75 trials of dPaCS-MD, which required an average simulation time of 11.2 ± 2.2 ns per trial. By setting the axis of the DNA duplex as the Z-axis and the binding side of p53-DBD on DNA as the + side of the X-axis, we found that dissociations took place along the +X and −Y directions (−Y directions) in 93% of the cases, while 7% of the cases moved along +X and +Y directions (+Y directions). Toward the −Y directions, p53-DBD dissociated first from the major groove and then detached from the minor groove, while unbinding from the minor groove occurred first in dissociations along the +Y directions. Analysis of the free energy landscape by MSM showed that loss of the minor groove interaction with p53-DBD toward the +Y directions incurred a relatively high energy cost (1.1 kcal/mol) upon a critical transition, whereas major groove detachment more frequently occurred with lower free energy costs. The standard binding free energy calculated from the free energy landscape was −10.9 ± 0.4 kcal/mol, which agrees with an experimental value of –11.1 kcal/mol. These results indicate that the dPaCS-MD/MSM combination can be a powerful tool to investigate dissociation mechanisms of two large molecules. Minor groove binding is mainly stabilized by R248, identified as the most important residue that tightly binds deep inside the minor groove. Analysis of the p53 key residues for DNA binding indicates high correlations with cancer-related mutations, confirming that impairment of the interactions between p53-DBD and DNA can be frequently related to cancer.

NMR studies of the R2 repeat and related peptide fragments of the DNA binding domain of c-Myb. New light on the structure and folding of R2.

1999 ◽  
Vol 96 (9/10) ◽  
pp. 1580-1584 ◽  
Author(s):  
I. Ségalas ◽  
S. Desjardins ◽  
H. Oulyadi ◽  
Y. Prigent ◽  
S. Tribouillard ◽  
...  
Keyword(s):  
Dna Binding ◽  
Binding Domain ◽  
Dna Binding Domain ◽  
Peptide Fragments ◽  
Nmr Studies ◽  
Related Peptide

Configurational Diffusion on a Locally Connected Correlated Energy Landscape; Application to Finite, Random Heteropolymers

1997 ◽  
Vol 7 (3) ◽  
pp. 395-421 ◽  
Author(s):  
Jin Wang ◽  
Steven S. Plotkin ◽  
Peter G. Wolynes
Keyword(s):  
Energy Landscape
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