Butyl Pocket Formation in the Vitamin D Receptor Strongly Affects the Agonistic or Antagonistic Behavior of Ligands

Yoshimoto, Nobuko; Sakamaki, Yuta; Haeta, Minoru; Kato, Akira; Inaba, Yuka; Itoh, Toshimasa; Nakabayashi, Makoto; Ito, Nobuyasu; Yamamoto, Keiko

doi:10.1021/jm300230a

Cited by 23 publications

(27 citation statements)

References 44 publications

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“…Although the accommodation of such larger groups in the small cavity might not contribute significantly to stabilizing AF-2 for co-activator binding, it may provide opportunities to improve the compound binding affinity. This concept of converting an agonist into an antagonist by weakening or abolishing interactions between the ligand and the terminal helix 12 (AF-2) is reminiscent of VDR antagonists, which unlike their agonist counterparts, have insufficient interactions with residues in the AF-2 helix 42 , 43 .…”

Section: Resultsmentioning

confidence: 99%

SPA70 is a potent antagonist of human pregnane X receptor

et al. 2017

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Many drugs bind to and activate human pregnane X receptor (hPXR) to upregulate drug-metabolizing enzymes, resulting in decreased drug efficacy and increased resistance. This suggests that hPXR antagonists have therapeutic value. Here we report that SPA70 is a potent and selective hPXR antagonist. SPA70 inhibits hPXR in human hepatocytes and humanized mouse models and enhances the chemosensitivity of cancer cells, consistent with the role of hPXR in drug resistance. Unexpectedly, SJB7, a close analog of SPA70, is an hPXR agonist. X-ray crystallography reveals that SJB7 resides in the ligand-binding domain (LBD) of hPXR, interacting with the AF-2 helix to stabilize the LBD for coactivator binding. Differential hydrogen/deuterium exchange analysis demonstrates that SPA70 and SJB7 interact with the hPXR LBD. Docking studies suggest that the lack of the para-methoxy group in SPA70 compromises its interaction with the AF-2, thus explaining its antagonism. SPA70 is an hPXR antagonist and promising therapeutic tool.

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Section: Resultsmentioning

confidence: 99%

SPA70 is a potent antagonist of human pregnane X receptor

et al. 2017

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“…The compound with a butyl group induced the formation of a new cavity in the LBD (Fig. E, green) . Intriguingly, these ligands exhibited antagonistic activity, suggesting that expansion of the ligand‐binding pocket decreases the transcriptional activity.…”

Section: Discussionmentioning

confidence: 99%

Regulation of the vitamin D receptor by vitamin D lactam derivatives

et al. 2016

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The active metabolite of vitamin D 3 , 1a,25-dihydroxyvitamin D 3 , acts as a ligand for the vitamin D receptor (VDR) and activates VDR-mediated gene expression. Recently, we characterized 1a,25-dihydroxyvitamin D 3 -26,23-lactams (DLAMs), which mimic vitamin D 3 metabolites, as noncalcemic VDR ligands that barely activate the receptor. In this study, we present structural insights onto the regulation of VDR function by DLAMs. X-ray crystallographic analysis revealed that DLAMs induced a large conformational change in the loop region between helices H6 and H7 in the VDR ligand-binding domain. Our structural analysis suggests that targeting of the loop region may be a new mode of VDR regulation. Since VDR activated by 1,25(OH) 2 D 3 coordinates calcium absorption in the gut and bone remodeling to maintain adequate serum calcium concentrations, this ligand-dependent receptor function is important to prevent rickets, osteomalacia, and hypocalcemic tetany [6]. Thus, many 1,25(OH) 2 D 3 derivatives have been developed as drug candidates for these diseases [7][8][9]. However, VDR activation by high-dose treatment with those types of ligands leads to excessive skeletal calcium release, increases intestinal calcium absorption, and decreases renal calcium excretion, thereby resulting in lethal levels of calcium in the bloodstream, known as hypercalcemia [10].We developed a new type of ligand, 1a,25-dihydroxyvitamin D 3 -26,23-lactams (DLAMs), which

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“…The X‐ray structure of VDR in complex with 22 S ‐butyl‐25,26,27‐trinor‐1α,24‐dihydroxyvitamin D 3 showed that the compound forms poor hydrophobic contacts with the AF‐2 helix and, surprisingly, induces the formation of a small cavity within the ligand‐binding pocket to accommodate the butyl moiety; this ligand‐induced structural feature in the canonical VDR LBD had not been observed previously . The cavity, known as the “butyl pocket,” is believed to be strongly linked to the agonistic or antagonistic behavior of the ligand, and it serves to demonstrate that flexible regions in the LBD can be exploited for fine‐tuning NR activity . Based on structure‐activity relation studies, the 22 S ‐hexyl analog was originally designed to be a more potent antagonist than its progenitors.…”

Section: Current Status Of Pxr Antagonist Development Challenges Anmentioning

confidence: 87%

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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Butyl Pocket Formation in the Vitamin D Receptor Strongly Affects the Agonistic or Antagonistic Behavior of Ligands

Cited by 23 publications

References 44 publications

SPA70 is a potent antagonist of human pregnane X receptor

SPA70 is a potent antagonist of human pregnane X receptor

Regulation of the vitamin D receptor by vitamin D lactam derivatives

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

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