Apo- and Antagonist-Binding Structures of Vitamin D Receptor Ligand-Binding Domain Revealed by Hybrid Approach Combining Small-Angle X-ray Scattering and Molecular Dynamics

Anami, Yasuaki; Ekimoto, Toru; Egawa, Daichi; Itoh, Toshimasa; Ikeguchi, Mitsunori

doi:10.1021/acs.jmedchem.6b00682

Cited by 25 publications

(46 citation statements)

References 75 publications

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“…For computational convenience, we introduced a scaling factor c vρ by replacing v i CG ρ s in Eq. (8). Taken together, Eq.…”

Section: Computational Details Of the Scattering Intensity From Cg Momentioning

confidence: 78%

“…The excess scattering intensity of a CG model, I CG (q), including effects of the excluded volume and the hydration shell was developed by Eqs. (1)-(4), (8) and (10). In the CG-MD-SAXS method, I CG (q) is averaged over a large number of snapshot structures in CG-MD trajectories.…”

Section: Computational Details Of the Scattering Intensity From Cg Momentioning

confidence: 99%

“…The two parameters of v i CG ρ s and w defined in Eqs. (8) and (10) are adjustable parameters. For computational convenience, we introduced a scaling factor c vρ by replacing v i CG ρ s in Eq.…”

Section: Computational Details Of the Scattering Intensity From Cg Momentioning

confidence: 99%

“…First, the scattering factors of CG particles were determined by Eqs. (4), (8) and (9) using high-resolution crystal structures. Next, the radii of the Gaussian spheres, α i , were determined by minimization of the difference between the CG scattering factors calculated by our formulation, f i CG_vac_ex (q), and by the formulation of Yang, S., et al [13], f i ′ CG_vac_ex (q).…”

Section: Determination Of Scattering Factors For Cg Particlesmentioning

confidence: 99%

“…For nucleic acids, the base, sugar and phosphate of nucleotides are represented as three different CG particles, respectively. First, the scattering factors of the CG particles for 20 amino acids, and a structure ensemble of proteins [7,8].…”

mentioning

confidence: 99%

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Combination of coarse-grained molecular dynamics simulations and small-angle X-ray scattering experiments

et al. 2019

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The combination of molecular dynamics (MD) simulations and small-angle X-ray scattering (SAXS), called the MD-SAXS method, is efficient for investigating protein dynamics. To overcome the time-scale limitation of allatom MD simulations, coarse-grained (CG) representations are often utilized for biomolecular simulations. In this study, we propose a method to combine CG MD simulations with SAXS, termed the CG-MD-SAXS method. In the CG-MD-SAXS method, the scattering factors of CG particles for proteins and nucleic acids are evaluated using high-resolution structural data in the Protein Data Bank, and the excluded volume and the hydration shell are modeled using two adjustable parameters to incorporate solvent effects. To avoid overfitting, only the two parameters are adjusted for an entire structure ensemble. To verify the developed method, theoretical SAXS profiles for various proteins, DNA/RNA, and a protein-RNA complex are compared with both experimental profiles and theoretical profiles obtained by the all-atom representation. In the present study, we applied the CG-MD-SAXS method to the Swi5-Sfr1 complex and three types of nucleosomes to obtain reliable ensemble models consistent with the experimental SAXS data.

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“…For computational convenience, we introduced a scaling factor c vρ by replacing v i CG ρ s in Eq. (8). Taken together, Eq.…”

Section: Computational Details Of the Scattering Intensity From Cg Momentioning

confidence: 78%

Section: Computational Details Of the Scattering Intensity From Cg Momentioning

confidence: 99%

Section: Computational Details Of the Scattering Intensity From Cg Momentioning

confidence: 99%

Section: Determination Of Scattering Factors For Cg Particlesmentioning

confidence: 99%

mentioning

confidence: 99%

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Combination of coarse-grained molecular dynamics simulations and small-angle X-ray scattering experiments

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When Two Become One: Conformational Changes in FXR/RXR Heterodimers Bound to Steroidal Antagonists

et al. 2022

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Farnesoid X receptor (FXR) is a nuclear receptor with an essential role in regulating bile acid synthesis and cholesterol homeostasis. FXR activation by agonists is explained by an αAF-2-trapping mechanism; however, antagonism mechanisms are diverse. We discuss microsecond molecular dynamics (MD) simulations investigating our recently reported FXR antagonists 2a and 2 h. We study the antagonist-induced conformational changes in the FXR ligand-binding domain, when compared to the synthetic (GW4064) or steroidal (chenodeoxycholic acid, CDCA) FXR agonists in the FXR monomer or FXR/RXR hetero-dimer r, and in the presence and absence of the coactivator. Our MD data suggest ligand-specific influence on conformations of different FXR-LBD regions, including the α5/α6 region, αAF-2, and α9-11. Changes in the heterodimerization interface induced by antagonists seem to be associated with αAF-2 destabilization, which prevents both co-activator and corepressor recruitment. Our results provide new insights into the conformational behaviour of FXR, suggesting that FXR antagonism/agonism shift requires a deeper assessment than originally proposed by crystal structures.

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Strategies for developing pregnane X receptor antagonists: Implications from metabolism to cancer

Chai

Wright

Chen

2019

Medicinal Research Reviews

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Pregnane X receptor (PXR) is a ligand-activated nuclear receptor (NR) that was originally identified as a master regulator of xenobiotic detoxification. It regulates the expression of drug-metabolizing enzymes and transporters to control the degradation and excretion of endobiotics and xenobiotics, including therapeutic agents. The metabolism and disposition of drugs might compromise their efficacy and possibly cause drug toxicity and/or drug resistance. Because many drugs can promiscuously bind and activate PXR, PXR antagonists might have therapeutic value in preventing and overcoming drug-induced PXR-mediated drug toxicity and drug resistance. Furthermore, PXR is now known to have broader cellular functions, including the regulation of cell proliferation, and glucose and lipid metabolism. Thus, PXR might be involved in human diseases such as cancer and metabolic diseases. The importance of PXR antagonists is discussed in the context of the role of PXR in xenobiotic sensing and other disease-related pathways. This review focuses on the development of PXRantagonists, which has been hampered by the promiscuity of PXR ligand binding. However, substantial progress has been made in recent years, suggesting that it is feasible to develop selective PXR antagonists. We discuss the current status, challenges, and strategies in developing selective PXR antagonists. The strategies are based on the molecular mechanisms of antagonism in related NRs that can be applied to the design of PXR antagonists, primarily driven by structural information.The nuclear receptor (NR) pregnane X receptor (PXR, NR1I2) plays a prominent role in the detoxification system that humans and other organisms utilize to eliminate endobiotics such as steroid hormones, bile acids, and glucose and xenobiotics such as therapeutic agents. Upon the binding of a ligand, PXR transcriptionally upregulates the expression of drug-metabolizing enzymes and transporters, leading to the metabolism and, ultimately, clearance of endobiotics and xenobiotics. These chemicals undergo biotransformation and disposition through a series of processes comprising oxidation and conjugation reactions (involving cytochrome P450 enzymes [CYPs], such as CYP3A4, UDP-glucuronosyltransferases, and glutathione-S-transferases, sulfotransferases) and active efflux (involving the transporter proteins multidrug resistance proteins and multidrug resistance-associated proteins). [1][2][3][4] PXR and the detoxification system represent a double-edged sword: Although detoxification serves as a beneficial protection mechanism against toxic compounds, it also compromises therapeutic outcomes by decreasing drug efficacy and possibly inducing drug toxicity and resistance. Therefore, a balance between PXR transcriptional activation and repression is needed, not only to maintain appropriate physiologic levels of endogenous chemicals but also to achieve optimal therapeutic efficacy with fewer drug-induced toxicities. Because of its important role in regulating drug efficacy and drug toxicity, as wel...

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Apo- and Antagonist-Binding Structures of Vitamin D Receptor Ligand-Binding Domain Revealed by Hybrid Approach Combining Small-Angle X-ray Scattering and Molecular Dynamics

Cited by 25 publications

References 75 publications

Combination of coarse-grained molecular dynamics simulations and small-angle X-ray scattering experiments

Combination of coarse-grained molecular dynamics simulations and small-angle X-ray scattering experiments

When Two Become One: Conformational Changes in FXR/RXR Heterodimers Bound to Steroidal Antagonists

Strategies for developing pregnane X receptor antagonists: Implications from metabolism to cancer

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