Allosteric Pathways in the PPARγ-RXRα nuclear receptor complex

Ricci, Clarisse Gravina; Silveira, Rodrigo L.; Rivalta, Ivan; Batista, Víctor S.; Skaf, Munir S.

doi:10.1038/srep19940

Cited by 44 publications

(60 citation statements)

References 75 publications

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“…In order to identify the interdependent motions of the protein regions moving in lockstep (i.e., as characterized by a CC ij > 0) or showing opposite motions (CC ij < 0), we have computed a per-residue correlation score (Cs i ), which is a measure of the number and intensity of the correlated and anticorrelated motions for each residue (full details in the Supporting Information). 21 Per-residue Cs i have been accumulated over each protein domain and plotted as a two-by-two matrix, such detailing the interdomain correlations (Figure 5). In the apo form, the Cas9 protein domains show specific patterns of correlated/anticorrelated motions with respect to each other, which characterize their tendency to move concertedly in different directions.…”

Section: Resultsmentioning

confidence: 99%

Striking Plasticity of CRISPR-Cas9 and Key Role of Non-target DNA, as Revealed by Molecular Simulations

et al. 2016

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The CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 system recently emerged as a transformative genome-editing technology that is innovating basic bioscience and applied medicine and biotechnology. The endonuclease Cas9 associates with a guide RNA to match and cleave complementary sequences in double stranded DNA, forming an RNA:DNA hybrid and a displaced non-target DNA strand. Although extensive structural studies are ongoing, the conformational dynamics of Cas9 and its interplay with the nucleic acids during association and DNA cleavage are largely unclear. Here, by employing multi-microsecond time scale molecular dynamics, we reveal the conformational plasticity of Cas9 and identify key determinants that allow its large-scale conformational changes during nucleic acid binding and processing. We show how the “closure” of the protein, which accompanies nucleic acid binding, fundamentally relies on highly coupled and specific motions of the protein domains, collectively initiating the prominent conformational changes needed for nucleic acid association. We further reveal a key role of the non-target DNA during the process of activation of the nuclease HNH domain, showing how the nontarget DNA positioning triggers local conformational changes that favor the formation of a catalytically competent Cas9. Finally, a remarkable conformational plasticity is identified as an intrinsic property of the HNH domain, constituting a necessary element that allows for the HNH repositioning. These novel findings constitute a reference for future experimental studies aimed at a full characterization of the dynamic features of the CRISPR-Cas9 system, and—more importantly—call for novel structure engineering efforts that are of fundamental importance for the rational design of new genome-engineering applications.

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Section: Resultsmentioning

confidence: 99%

Striking Plasticity of CRISPR-Cas9 and Key Role of Non-target DNA, as Revealed by Molecular Simulations

et al. 2016

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“…Previous studies suggested that fatty acid metabolites activate PPARγ through structural rearrangements of the Ω-loop and distinct degrees of the receptor mediated cellular activities originate from structural differences in this region33. On the basis of this reasoning, it is conceivable to argue that the activity of partial agonists may stem from a mechanism distinct from that of full agonists with H3, β-sheet and the Ω-loop directly involved in this modality3740474849. Interestingly, and at odds with other partial agonists, 1 covalently binds to the C285 present in the PPARγ-LBD through a α,β-unsaturated ketone.…”

Section: Discussionmentioning

confidence: 99%

A compound-based proteomic approach discloses 15-ketoatractyligenin methyl ester as a new PPARγ partial agonist with anti-proliferative ability

Vasaturo

Fiengo

Tommasi

et al. 2017

Sci Rep

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Proteomics based approaches are emerging as useful tools to identify the targets of bioactive compounds and elucidate their molecular mechanisms of action. Here, we applied a chemical proteomic strategy to identify the peroxisome proliferator-activated receptor γ (PPARγ) as a molecular target of the pro-apoptotic agent 15-ketoatractyligenin methyl ester (compound 1). We demonstrated that compound 1 interacts with PPARγ, forms a covalent bond with the thiol group of C285 and occupies the sub-pocket between helix H3 and the β-sheet of the ligand-binding domain (LBD) of the receptor by Surface Plasmon Resonance (SPR), mass spectrometry-based studies and docking experiments. 1 displayed partial agonism of PPARγ in cell-based transactivation assays and was found to inhibit the AKT pathway, as well as its downstream targets. Consistently, a selective PPARγ antagonist (GW9662) greatly reduced the anti-proliferative and pro-apoptotic effects of 1, providing the molecular basis of its action. Collectively, we identified 1 as a novel PPARγ partial agonist and elucidated its mode of action, paving the way for therapeutic strategies aimed at tailoring novel PPARγ ligands with reduced undesired harmful side effects.

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“…Unlike a conventional analysis which calculates the covariance matrix of C α atoms (a two-point correlation analysis), 28,29 CAMERRA performs a higher order (4-point) correlation analysis, which is a new and clearer way to locate the correlated movements among four residues and the allosteric communications. 36 Particularly, we have applied CAMERRA to uncover the negative allosteric mechanism of the RXR:TR complex in a previous study 36 and the positive allostery of ricin subunits in another study.…”

Section: Introductionmentioning

confidence: 99%

The Promiscuity of Allosteric Regulation of Nuclear Receptors by Retinoid X Receptor

Clark¹,

Wilder²,

Grayson³

et al. 2016

J. Phys. Chem. B

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The promiscuous protein retinoid X receptor (RXR) displays essential allosteric regulation of several members in the nuclear hormone receptor superfamily via heterodimerization and (anti)cooperative binding of cognate ligands. Here, the structural basis of the positive allostery of RXR and constitutive androstane receptor (CAR) is revealed. In contrast, a similar computational approach had previously revealed the mechanism for negative allostery in the complex of RXR and thyroid receptor (TR). By comparing the positive and negative allostery of RXR complexed with CAR and TR respectively, we reported the promiscuous allosteric control involving RXR. We characterize the allosteric mechanism by expressing the correlated dynamics of selected residue–residue contacts which was extracted from atomistic molecular dynamics simulation and statistical analysis. While the same set of residues in the binding pocket of RXR may initiate the residue–residue interaction network, RXR uses largely different sets of contacts (only about one-third identical) and allosteric modes to regulate TR and CAR. The promiscuity of RXR control may originate from multiple factors, including (1) the frustrated fit of cognate ligand 9c to the RXR binding pocket and (2) the different ligand-binding features of TR (loose) versus CAR (tight) to their corresponding cognate ligands.

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Allosteric Pathways in the PPARγ-RXRα nuclear receptor complex

Cited by 44 publications

References 75 publications

Striking Plasticity of CRISPR-Cas9 and Key Role of Non-target DNA, as Revealed by Molecular Simulations

Striking Plasticity of CRISPR-Cas9 and Key Role of Non-target DNA, as Revealed by Molecular Simulations

A compound-based proteomic approach discloses 15-ketoatractyligenin methyl ester as a new PPARγ partial agonist with anti-proliferative ability

The Promiscuity of Allosteric Regulation of Nuclear Receptors by Retinoid X Receptor

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