22S-Butyl-1α,24R-dihydroxyvitamin D3: Recovery of vitamin D receptor agonistic activity

Inaba, Yuka; Nakabayashi, Makoto; Itoh, Toshimasa; Yoshimoto, Nobuko; Ikura, Teikichi; Ito, Nobuyasu; Shimizu, Masato; Yamamoto, Keiko

doi:10.1016/j.jsbmb.2010.02.033

Cited by 19 publications

(18 citation statements)

References 10 publications

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“…These considerations are consistent with the observation that 1 does not recruit either RXR or the SRC-1 peptide. 39 Based on these results, we conclude that the mechanism of VDR antagonistic behavior varies. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 28 In conclusion, we designed and synthesized vitamin D analogues 2a,b-6a,b and evaluated their biological activities.…”

Section: Discussionmentioning

confidence: 77%

Helix12-Stabilization Antagonist of Vitamin D Receptor

et al. 2016

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To develop strong vitamin D receptor (VDR) antagonists and reveal their antagonistic mechanism, we designed and synthesized vitamin D analogues with bulky side chains based on the "active antagonist" concept in which antagonist prevents helix 12 (H12) folding. Of the synthesized analogues, compounds 3a and 3b showed strong antagonistic activity. Dynamic hydrogen/deuterium exchange coupled with mass spectrometry (HDX-MS) and static X-ray crystal structure analyses indicated that compound 3a stabilizes H11-H12 but displaces H6-H7 so that 3a is a novel rather than "active" or "passive" type of antagonist. We classified 3a as a third type of antagonist and called it "H11-H12 stabilization antagonist". HDX-MS analysis indicated that antagonist 3b is an "active" antagonist. To date there are no reports relating to nuclear receptor antagonist that strongly stabilizes H12. In this study, we found first VDR antagonist that stabilizes H12 and we showed that antagonistic mechanism is diverse depending on each antagonist structure. Additionally, HDX-MS was proven to be very useful for investigations of protein structure alterations resulting from ligand binding.

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Section: Discussionmentioning

confidence: 77%

Helix12-Stabilization Antagonist of Vitamin D Receptor

et al. 2016

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“…The additional modification of the 22S-butyl-1 ,25 (OH) 2 D 3 antagonist to 22S-butyl-1 ,24R(OH) 2 D 3 , which contains the three carbons absent from the side chain of 22S-butyl-1 ,25(OH) 2 D 3 , shows a weak but restored agonistic activity [144]. The structural determinants of this reversed property is attributed to the restoration of the conserved interactions of the ligand with residues (of the rat VDR-LBD), such as H301 and H393, the original position of L305 and a general increase in the stability of the complex.…”

Section: Analogues With Two Side Chainsmentioning

confidence: 99%

Current Status of Vitamin D Signaling and Its Therapeutic Applications

Carlberg

Molnár

2012

CTMC

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Vitamin D and in particular its biologically most active metabolite, 1α,25-dihydroxyvitamin D₃ (1α,25(OH)₂D₃), are central endocrine molecules that influence many aspects of human physiology, which are not only the well-known calcium and phosphorus up-take and transport controlling bone formation, but also the control of immune functions and of cellular growth and differentiation. Basically all actions of 1α,25(OH)₂D₃ are mediated by the transcription factor vitamin D receptor (VDR). The crystal structure of the VDR and detailed knowledge on its molecular interactions with the ligand provide significant insight into the mechanisms of vitamin D signaling. This applies also on the action of the huge number of synthetic 1α,25(OH)₂D₃ analogues, which have been developed with the goal of a therapeutic application in hyper-proliferative diseases, such as psoriasis, benign prostate hyperplasia and different types of cancer, in immune functions, such as autoimmune diseases and microbial infections, or in bone disorders, such as osteoporosis. Moreover, detailed investigations on many VDR target genes and in particular the recently available genome-wide view on vitamin D signaling allows a more complete view on the potential of the nuclear hormone. In this review we discuss the latest insight into vitamin D signaling in context with the most prominent 1α,25(OH)₂D₃ analogues.

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“…Large ligands could collide with helix 12 and destabilize the active conformation. Indeed, several larger ligands have been reported to show antagonistic activity instead of agonistic activity ( 32,37 ).…”

Section: Structure Of the Med1 Peptidementioning

confidence: 99%

Crystal structures of complexes of vitamin D receptor ligand-binding domain with lithocholic acid derivatives

Masuno

Ikura

Morizono

et al. 2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org super family ( 15 ). When 1,25(OH) 2 D 3 is bound to VDR, it activates it by inducing conformational changes. The activated complex, VDR/1,25(OH) 2 D 3 , binds as a heterodimer with the retinoid X receptor (RXR) to vitamin D response elements located in the promoter region of the target genes. Recruitment of coactivator proteins to this heterodimer is also essential to the transactivation. However, clinical use of 1,25(OH) 2 D 3 is limited because therapeutic doses can give rise to signifi cant hypercalciuria and hypercalcemia ( 16 ). A number of synthetic ligands to VDR have been developed for medical use; however, most of them can also cause similar problems because they are derived from 1,25(OH) 2 D 3 .Several synthetic compounds without the vitamin D 3 scaffold have been reported to bind to VDR and have VDR-modulating activities, including growth inhibition of cancer cells and keratinocytes and induction of leukemic cell differentiation, with less calcium mobilization side effects than 1,25(OH) 2 D 3 ( 17 ). Therefore, these synthetic compounds are expected to be therapeutics for cancer, leukemia, and psoriasis. Subsequently, Makishima et al. discovered that secondary bile acids, including lithocholic acid (LCA) and its derivatives, also behaved as VDR agonists (18)(19)(20). LCA acts as a detergent to stabilize fats for absorption, and it has been implicated in human and experimental animal carcinogenesis. However, the agonistic behavior of LCA as a ligand recognized by VDR was not common knowledge because the structure of LCA is completely different from that of vitamin D 3 . Additional studies showed that VDR had dual functions as a metabolic sensor of bile acids and as an endocrine receptor for 1,25(OH) 2 D 3 . , regulates calcium homeostasis ( 1 ). It also promotes cellular differentiation, inhibits cellular proliferation, and suppresses the immune system ( 2-7 ). It has been used clinically to treat renal osteodystrophy, vitamin D-dependent rickets type I, and X-linked hypophosphatemic rickets, among other conditions (8)(9)(10)(11)(12)(13)(14). Most of its effects are mediated by its specifi c binding to the vitamin D receptor (VDR), which is a member of nuclear receptor (NR) Abstract Manuscript

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22S-Butyl-1α,24R-dihydroxyvitamin D3: Recovery of vitamin D receptor agonistic activity

Cited by 19 publications

References 10 publications

Helix12-Stabilization Antagonist of Vitamin D Receptor

Helix12-Stabilization Antagonist of Vitamin D Receptor

Current Status of Vitamin D Signaling and Its Therapeutic Applications

Crystal structures of complexes of vitamin D receptor ligand-binding domain with lithocholic acid derivatives

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