Deciphering Modern Glucocorticoid Cross-pharmacology Using Ancestral Corticosteroid Receptors

Kohn, Jeffrey A.; Deshpande, K. Y.; Ortlund, Eric A.

doi:10.1074/jbc.m112.346411

Cited by 21 publications

(36 citation statements)

References 31 publications

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“…Thornton and coworkers have generated crystal structures of ancestral proteins that along branches of a phylogenetic tree show conserved and changed binding functions. 35–38 While the structures are of complexes rather than unbound, comparisons of the normal modes and RMSD of the static structures can be evaluated along a branch estimated as 0.10 substitutions per site without a change of binding partner and along a branch with length 0.14 substitutions per site with a change of binding partner. The first branch shows a static RMSD of 0.51 Å and a normal modes overlap of 0.72.…”

Section: Resultsmentioning

confidence: 99%

A Phylogenetic Analysis of Normal Modes Evolution in Enzymes and Its Relationship to Enzyme Function

Lai

Jin

Kubelka

et al. 2012

Journal of Molecular Biology

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Since the dynamic nature of protein structures is essential for enzymatic function, it is expected that the functional evolution can be inferred from the changes in the protein dynamics. However, dynamics can also diverge neutrally with sequence substitution between enzymes without changes of function. In this study, a phylogenetic approach is implemented to explore the relationship between enzyme dynamics and function through evolutionary history. Protein dynamics are described by normal mode analysis based on a simplified harmonic potential force field applied to the reduced Cα representation of the protein structure while enzymatic function is described by Enzyme Commission (EC) numbers. Similarity of the binding pocket dynamics at each branch of the protein family’s phylogeny was analyzed in two ways: 1) explicitly by quantifying the normal mode overlap calculated for the reconstructed ancestral proteins at each end and 2) implicitly using a diffusion model to obtain the reconstructed lineage-specific changes in the normal modes. Both explicit and implicit ancestral reconstruction identified generally faster rates of change in dynamics compared with the expected change from neutral evolution at the branches of potential functional divergences for the alpha-amylase, D-isomer specific 2-hydroxyacid dehydrogenase, and copper-containing amine oxidase protein families. Normal modes analysis added additional information over just comparing the RMSD of static structures. However, the branch-specific changes were not statistically significant compared to background function-independent neutral rates of change of dynamic properties and blind application of the analysis would not enable prediction of changes in enzyme specificity.

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Section: Resultsmentioning

confidence: 99%

A Phylogenetic Analysis of Normal Modes Evolution in Enzymes and Its Relationship to Enzyme Function

Lai

Jin

Kubelka

et al. 2012

Journal of Molecular Biology

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“…MR is highly homologous to glucocorticoid receptor (GR) and both receptors are ligand-dependent transcription factors (Arriza et al, 1987; Kohn et al, 2012). MR and GR share 94% primary sequence homology in the DNA binding domain, and both receptors share the same HREs in several genes, including αENaC (Arriza et al, 1987; Chen, 1999; Mick et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Role of Per1 and the mineralocorticoid receptor in the coordinate regulation of αENaC in renal cortical collecting duct cells

Richards¹,

Jeffers²,

All³

et al. 2013

Front. Physiol.

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Renal function and blood pressure (BP) exhibit a circadian pattern of variation, but the molecular mechanism underlying this circadian regulation is not fully understood. We have previously shown that the circadian clock protein Per1 positively regulates the basal and aldosterone-mediated expression of the alpha subunit of the renal epithelial sodium channel (αENaC). The mechanism of this regulation has not been determined however. To further elucidate the mechanism of mineralocorticoid receptor (MR) and Per1 action, site-directed mutagenesis, DNA pull-down assays and chromatin immunoprecipitation (ChIP) methods were used to investigate the coordinate regulation of αENaC by Per1 and MR. Mutation of two circadian response E-boxes in the human αENaC promoter abolished both basal and aldosterone-mediated promoter activity. DNA pull down assays demonstrated the interaction of both MR and Per1 with the E-boxes from the αENaC promoter. These observations were corroborated by ChIP experiments showing increased occupancy of MR and Per1 on an E-box of the αENaC promoter in the presence of aldosterone. This is the first report of an aldosterone-mediated increase in Per1 on a target gene promoter. Taken together, these results demonstrate the novel finding that Per1 and MR mediate the aldosterone response of αENaC through DNA/protein interaction in renal collecting duct cells.

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“…In the case of mometasone furoate, it was found that there is a dipole–dipole interaction between the C21 Cl and an asparagine residue in the binding pocket AncGR2-Asn33 that contributes to the high affinity of binding [24]. …”

Section: Alkyl Halides In Medicinementioning

confidence: 99%

Chiral Alkyl Halides: Underexplored Motifs in Medicine

2016

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While alkyl halides are valuable intermediates in synthetic organic chemistry, their use as bioactive motifs in drug discovery and medicinal chemistry is rare in comparison. This is likely attributable to the common misconception that these compounds are merely non-specific alkylators in biological systems. A number of chlorinated compounds in the pharmaceutical and food industries, as well as a growing number of halogenated marine natural products showing unique bioactivity, illustrate the role that chiral alkyl halides can play in drug discovery. Through a series of case studies, we demonstrate in this review that these motifs can indeed be stable under physiological conditions, and that halogenation can enhance bioactivity through both steric and electronic effects. Our hope is that, by placing such compounds in the minds of the chemical community, they may gain more traction in drug discovery and inspire more synthetic chemists to develop methods for selective halogenation.

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Deciphering Modern Glucocorticoid Cross-pharmacology Using Ancestral Corticosteroid Receptors

Cited by 21 publications

References 31 publications

A Phylogenetic Analysis of Normal Modes Evolution in Enzymes and Its Relationship to Enzyme Function

A Phylogenetic Analysis of Normal Modes Evolution in Enzymes and Its Relationship to Enzyme Function

Role of Per1 and the mineralocorticoid receptor in the coordinate regulation of αENaC in renal cortical collecting duct cells

Chiral Alkyl Halides: Underexplored Motifs in Medicine

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