Shriyansh Srivastava, A M Vishnu, Rakesh Thakur, Ashutosh Srivastava
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引用次数: 0
Abstract
REV-ERBβ is a nuclear receptor (NR) with heme as an endogenous ligand that regulates its transcriptional activity. With a key role in cellular functions such as glucose metabolism, immune response, and dysregulation in pathologies such as Type-2 diabetes mellitus and obesity, small molecule agonists and antagonists targeting REV-ERBs have been discovered. However, due to a lack of crystal structures in complex with these compounds, the structural and dynamical basis of these activities still remains elusive and hinders the rational design of molecules targeting REV-ERB. Using molecular dynamics simulations and docking studies, we have characterized the dynamics of REV-ERBβ ligand-binding domain (LBD) in different conformational states. The presence of heme in the binding pocket within LBD was found to dampen its dynamics as well as nuclear co-repressor (NCoR) peptide binding. We further show that the binding of the antagonist destabilizes the NCoR peptide binding to LBD mediated by loss of interactions with residues at the NCoR-REV-ERBβ interface. These findings could be utilized to design molecular scaffolds with better activity and selectivity against REV-ERBβ.
期刊介绍:
PROTEINS : Structure, Function, and Bioinformatics publishes original reports of significant experimental and analytic research in all areas of protein research: structure, function, computation, genetics, and design. The journal encourages reports that present new experimental or computational approaches for interpreting and understanding data from biophysical chemistry, structural studies of proteins and macromolecular assemblies, alterations of protein structure and function engineered through techniques of molecular biology and genetics, functional analyses under physiologic conditions, as well as the interactions of proteins with receptors, nucleic acids, or other specific ligands or substrates. Research in protein and peptide biochemistry directed toward synthesizing or characterizing molecules that simulate aspects of the activity of proteins, or that act as inhibitors of protein function, is also within the scope of PROTEINS. In addition to full-length reports, short communications (usually not more than 4 printed pages) and prediction reports are welcome. Reviews are typically by invitation; authors are encouraged to submit proposed topics for consideration.