REV-ERBβ Binding Pocket Dynamics With Implications for Rational Design of Small Molecule Modulators.

IF 2.8 4区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
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.

REV-ERBβ结合袋动力学及其对小分子调节剂合理设计的启示。
REV-ERBβ是一种以血红素为内源性配体调节其转录活性的核受体(NR)。针对REV-ERBs的小分子激动剂和拮抗剂在细胞功能如葡萄糖代谢、免疫反应和2型糖尿病和肥胖等病理失调中起着关键作用。然而,由于这些复合物缺乏晶体结构,这些活性的结构和动力学基础仍然难以捉摸,这阻碍了靶向REV-ERB分子的合理设计。通过分子动力学模拟和对接研究,研究了REV-ERBβ配体结合域(LBD)在不同构象状态下的动力学特性。研究发现,在LBD的结合口袋中存在血红素可以抑制其动力学以及核共抑制因子(NCoR)肽的结合。我们进一步表明,拮抗剂的结合通过NCoR- rev - erbβ界面残基的相互作用丧失介导的NCoR肽与LBD的结合不稳定。这些发现可用于设计具有更好活性和选择性的REV-ERBβ分子支架。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Proteins-Structure Function and Bioinformatics
Proteins-Structure Function and Bioinformatics 生物-生化与分子生物学
CiteScore
5.90
自引率
3.40%
发文量
172
审稿时长
3 months
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.
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