Crystal structure of the vitamin D nuclear receptor ligand binding domain in complex with a locked side chain analog of calcitriol

Rochel, Natacha; Hourai, Shinji; Pérez-García, Xenxo; Rumbo, Antonio; Mouriño, Antonio; Moras, Dino

doi:10.1016/j.abb.2007.01.031

Cited by 35 publications

(28 citation statements)

References 18 publications

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“…Two more residues at the C-terminal end (Glu421 and Ile422) were also undetectable in the complexes with LCA and 3-keto LCA. Most of these missing residues were previously reported as invisible in studies of other ternary complexes of VDR and are likely a characteristic common to crystals of VDR complexes (23)(24)(25)(26)(27)(28)(29)(30)(31).…”

Section: Structures Of the Ligands And Their Interactions With Vdr-ldbmentioning

confidence: 99%

“…1 ) to investigate how LCA and its derivatives bind to VDR and how they act as the agonists. The structures reveal that LCA and its derivatives bind to the same ligand-binding pocket (LBP) of VDR that 1,25(OH) 2 D 3 binds to (23)(24)(25)(26)(27)(28)(29)(30)(31), but in the opposite orientation. Comparison of these structures also show how LCA and its derivatives mimic 1,25(OH) 2 D 3 and give insight into how the C-3 substituents on the A-ring affect the activity of each ligand.…”

Section: Overall Structures Of the Ternary Complexesmentioning

confidence: 99%

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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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Section: Structures Of the Ligands And Their Interactions With Vdr-ldbmentioning

confidence: 99%

Section: Overall Structures Of the Ternary Complexesmentioning

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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“…[14][15][16] Thus, it might be expected that a targeted specific form of 1,25-(OH) 2 D might influence the structure of the VDR in such a way that it would bind certain coactivators and not others and may lend specificity with regard to target gene responses. Rochel et al [17][18] and subsequently Vanhooke et al 19 have crystallized the ligand-binding domain (LBD) of the VDR with different analogs. Both groups found that, even with analogs of very divergent structures and activities, the crystalline structure of the LBD is unchanged by the ligand.…”

Section: Introductionmentioning

confidence: 99%

The development of a bone- and parathyroid-specific analog of vitamin D: 2-methylene-19-Nor-(20S)-1α,25-dihydroxyvitamin D3

DeLuca¹

2014

BoneKEy Reports

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The goal of synthetic chemists in the vitamin D field has been to produce an analog(s) of 1α,25-dihydroxyvitamin D3 (1,25-(OH)2D3) that is selective for a specific function. The accumulation of structure/function information has led to the synthesis of two analogs that are both selective and more potent than 1,25-(OH)2D3, that is, 2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D3 (2MD) and 2α-methyl-19-nor-(20S)-1α,25-dihydroxyvitamin D3 (2AMD). In vivo, the efficacy of 2MD is approximately equal to that of 1,25-(OH)2D3 in intestinal calcium transport but is 30- to 100-fold more active in bone mobilization. In vitro, 2MD supports new bone synthesis at 10(-12) M, whereas 1,25-(OH)2D3 is active at 10(-8) M. Similarly, 2MD is two orders of magnitude more potent than 1,25-(OH)2D3 in stimulating osteoclastogenesis and osteoclastic bone resorption. 2MD also markedly increases bone mass and bone strength of ovariectomized female rats. In postmenopausal women, 2MD significantly increases markers of both bone formation and resorption but has minimal effect on bone mass. Thus, in patients who are undergoing primarily remodeling rather than modeling (rat), the increased resorption largely counteracts the increased bone formation. So far, 2MD has not been tested for reduction of fractures in this population. However, its selectivity includes the parathyroid gland. Thus in the 5/6-nephrectomy model of chronic renal failure, 2MD is much more potent than currently available vitamin D compounds used to suppress secondary hyperparathyroidism of renal failure without causing hypercalcemia. It is currently in phase 2B trials in patients on dialysis.

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“…Vitamin D receptor (VDR), as a member of nuclear hormone receptor super family 1, widely exists in different species, such as mammals 2, birds 3, and different kinds of fishes 4–6. So far, people have extensively studied the ligand binding domain (LBD) of VDR complexed with different ligands 7–26. Moras and coworkers firstly crystallized the human VDR‐LBD with the natural hormone, 1α, 25‐dihydroxyvitamin D 3 (1α, 25(OH) 2 D 3 ) ( a in Scheme ), in the year 2000 7.…”

Section: Introductionmentioning

confidence: 99%

“…Moras and coworkers firstly crystallized the human VDR‐LBD with the natural hormone, 1α, 25‐dihydroxyvitamin D 3 (1α, 25(OH) 2 D 3 ) ( a in Scheme ), in the year 2000 7. Later, the VDR‐LBD crystal structures from other species complexed with 1α, 25(OH) 2 D 3 analogues were crystallized by several other groups 8–22.…”

Section: Introductionmentioning

confidence: 99%

Theoretical studies on the structural rearrangement of ligand binding pocket in human vitamin D receptor

Wang

Tang

Hou

et al. 2010

Int J of Quantum Chemistry

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ABSTRACT:The structural rearrangement of the ligand binding domain (LBD) of human Vitamin D receptor (hVDR) complexed with 1a, 25-dihydroxyvitamin D 3 (natural ligand) and its analogues (denoted as b and c) was studied by molecular dynamics (MD) simulations. MD simulations revealed that these ligands could induce different structural changes of LBD, in which 1a, 25-dihydroxyvitamin D 3 only led to a minute change, suggesting that LBD adopted its canonical active conformation upon binding the natural ligand, while b and c could provoke a clear structural rearrangement of the LBD. In complex of hVDR-LBD/b, it is found that helix 6 (H6) and subsequent loop 6-7 shift outward and the last turn of H11 shifts away from H12, which generate a new cavity at the bottom of binding pocket to accommodate the extra butyl group on the side chain of ligand b. As for hVDR-LBD/c, the steric exclusion of the second side chain of ligand c makes the N-terminal of H7 move outsides and C-terminal of H11 close to H12, expanding the bottom of the pocket. These calculation results agree well the experimental observations.

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Crystal structure of the vitamin D nuclear receptor ligand binding domain in complex with a locked side chain analog of calcitriol

Cited by 35 publications

References 18 publications

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

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

The development of a bone- and parathyroid-specific analog of vitamin D: 2-methylene-19-Nor-(20S)-1α,25-dihydroxyvitamin D3

Theoretical studies on the structural rearrangement of ligand binding pocket in human vitamin D receptor

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