A vitamin D-based strategy overcomes chemoresistance in prostate cancer.

Background And Purpose: Castration-resistant prostate cancer (CRPC) is a common male malignancy that requires new therapeutic strategies due to acquired resistance to its first-line treatment, docetaxel. The benefits of vitamin D on prostate cancer (PCa) progression have been previously reported. This study aimed to investigate the effects of vitamin D on chemoresistance in CRPC.

Molecular basis for different substrate-binding sites and chaperone functions of the BRICHOS domain.

Proteins can misfold into fibrillar or amorphous aggregates and molecular chaperones act as crucial guardians against these undesirable processes. The BRICHOS chaperone domain, found in several otherwise unrelated proproteins that contain amyloidogenic regions, effectively inhibits amyloid formation and toxicity but can in some cases also prevent non-fibrillar, amorphous protein aggregation. Here, we elucidate the molecular basis behind the multifaceted chaperone activities of the BRICHOS domain from the Bri2 proprotein.

Structural analysis and biological activities of C25-amino and C25-nitro vitamin D analogs.

Intense synthetic efforts have been directed towards the development of noncalcemic analogs of 1,25-dihydroxyvitamin D. We describe here the structural analysis and biological evaluation of two derivatives of 1,25-dihydroxyvitamin D with modifications limited to the replacement of the 25-hydroxyl group by a 25-amino or 25-nitro groups. Both compounds are agonists of the vitamin D receptor.

Vitamin D Analogs Bearing C-20 Modifications Stabilize the Agonistic Conformation of Non-Responsive Vitamin D Receptor Variants.

The Vitamin D receptor (VDR) plays a key role in calcium homeostasis, as well as in cell proliferation and differentiation. Among the large number of VDR ligands that have been developed, we have previously shown that BXL-62 and Gemini-72, two C-20-modified vitamin D analogs are highly potent VDR agonists. In this study, we show that both VDR ligands restore the transcriptional activities of VDR variants unresponsive to the natural ligand and identified in patients with rickets.

Cytosolic sequestration of the vitamin D receptor as a therapeutic option for vitamin D-induced hypercalcemia.

The bioactive vitamin D, 1α,25(OH)D, plays a central role in calcium homeostasis by controlling the activity of the vitamin D receptor (VDR) in various tissues. Hypercalcemia secondary to high circulating levels of vitamin D leads to hypercalciuria, nephrocalcinosis and renal dysfunctions. Current therapeutic strategies aim at limiting calcium intake, absorption and resorption, or 1α,25(OH)D synthesis, but are poorly efficient.

Molecular determinants of MED1 interaction with the DNA bound VDR-RXR heterodimer.

The MED1 subunit of the Mediator complex is an essential coactivator of nuclear receptor-mediated transcriptional activation. While structural requirements for ligand-dependent binding of classical coactivator motifs of MED1 to numerous nuclear receptor ligand-binding domains have been fully elucidated, the recognition of the full-length or truncated coactivator by full nuclear receptor complexes remain unknown. Here we present structural details of the interaction between a large part of MED1 comprising its structured N-terminal and the flexible receptor-interacting domains and the mutual heterodimer of the vitamin D receptor (VDR) and the retinoid X receptor (RXR) bound to their cognate DNA response element.

Structural Basis for α-Helix Mimicry and Inhibition of Protein-Protein Interactions with Oligourea Foldamers.

Efficient optimization of a peptide lead into a drug candidate frequently needs further transformation to augment properties such as bioavailability. Among the different options, foldamers, which are sequence-based oligomers with precise folded conformation, have emerged as a promising technology. We introduce oligourea foldamers to reduce the peptide character of inhibitors of protein-protein interactions (PPI).

Structural Analysis of VDR Complex with ZK168281 Antagonist.

Vitamin D receptor (VDR) antagonists prevent the VDR activation function helix 12 from folding into its active conformation, thus affecting coactivator recruitment and antagonizing the transcriptional regulation induced by 1α,25-dihydroxyvitamin D3. Here, we report the crystal structure of the zebrafish VDR ligand-binding domain in complex with the ZK168281 antagonist, revealing that the ligand prevents optimal folding of the C-terminal region of VDR. This interference was confirmed by hydrogen-deuterium exchange mass spectrometry (HDX-MS) in solution.

Structural analysis identifies an escape route from the adverse lipogenic effects of liver X receptor ligands.

Liver X receptors (LXRs) are attractive drug targets for cardiovascular disease treatment due to their role in regulating cholesterol homeostasis and immunity. The anti-atherogenic properties of LXRs have prompted development of synthetic ligands, but these cause major adverse effects-such as increased lipogenesis-which are challenging to dissect from their beneficial activities. Here we show that LXR compounds displaying diverse functional responses in animal models induce distinct receptor conformations.

1α,20S-Dihydroxyvitamin D Interacts with Vitamin D Receptor: Crystal Structure and Route of Chemical Synthesis.

1α,20S-Dihydroxyvitamin D3 [1,20S(OH)D], a natural and bioactive vitamin D3 metabolite, was chemically synthesized for the first time. X-ray crystallography analysis of intermediate 15 confirmed its 1α-OH configuration. 1,20S(OH)D interacts with the vitamin D receptor (VDR), with similar potency to its native ligand, 1α,25-dihydroxyvitamin D [1,25(OH)D] as illustrated by its ability to stimulate translocation of the VDR to the nucleus, stimulate VDRE-reporter activity, regulate VDR downstream genes (VDR, CYP24A1, TRPV6 and CYP27B1), and inhibit the production of inflammatory markers (IFNγ and IL1β).

Structure-activity relationship study of vitamin D analogs with oxolane group in their side chain.

Synthetic analogs of 1α,25-dihydroxyvitamin D (1,25(OH)D) have been developed with the goal of improving the biological profile of the natural hormone for therapeutic applications. Derivatives of 1,25(OH)D with the oxolane moiety branched in the side chain at carbon C20, act as Vitamin D nuclear Receptor (VDR) superagonists being several orders of magnitude more active than the natural ligand. Here, we describe the synthesis and biological evaluation of three diastereoisomers of (1S, 3R)-Dihydroxy-(20S)-[(2″-hydroxy-2″-propyl)-tetrahydrofuryl]-22,23,24,25,26,27-hexanor-1α-hydroxyvitamin D3, with different stereochemistry at positions C2 and C5 of the oxolane ring branched at carbon C22 (1, C2RC5S; 2, C2SC5R; 3, C2SC5S).

Structural analysis and biological activities of BXL0124, a gemini analog of vitamin D.

Gemini analogs of calcitriol, characterized by the extension of the C21-methyl group of calcitriol with a second chain, act as agonists of the vitamin D receptor (VDR). This second side chain of gemini is accommodated in a new cavity inside the VDR created by the structural rearrangement of the protein core. The resulting conformational change preserves the active state of the receptor and bestows gemini compounds with biological activities that exceed those of calcitriol.

Solution Behavior of the Intrinsically Disordered N-Terminal Domain of Retinoid X Receptor α in the Context of the Full-Length Protein.

Retinoid X receptors (RXRs) are transcription factors with important functions in embryonic development, metabolic processes, differentiation, and apoptosis. A particular feature of RXRs is their ability to act as obligatory heterodimerization partners of class II nuclear receptors. At the same time, these receptors are also able to form homodimers that bind to direct repeat separated by one nucleotide hormone response elements.

Structural Studies of Vitamin D Nuclear Receptor Ligand-Binding Properties.

The vitamin D nuclear receptor (VDR) and its natural ligand, 1α,25-dihydroxyvitamin D3 hormone (1,25(OH)2D3, or calcitriol), classically regulate mineral homeostasis and metabolism but also much broader range of biological functions, such as cell growth, differentiation, antiproliferation, apoptosis, adaptive/innate immune responses. Being widely expressed in various tissues, VDR represents an important therapeutic target in the treatment of diverse disorders. Since ligand binding is a key step in VDR-mediated signaling, numerous 1,25(OH)2D3 analogs have been synthesized in order to selectively modulate the receptor activity.

Carborane-based design of a potent vitamin D receptor agonist.

The vitamin D nuclear receptor (VDR) is a potential target for cancer therapy. It is expressed in many tumors and its ligand shows anticancer actions. To combine these properties with the application of boron neutron capture therapy (BNCT), we design and synthesize a potent VDR agonist based on the skeleton of the hormone 1α,25-dihydroxyvitamin D (1,25D) and an -carborane (dicarba--1,2-dodecaborane) at the end of its side chain.

A vitamin D receptor selectively activated by gemini analogs reveals ligand dependent and independent effects.

The bioactive form of vitamin D [1,25(OH)2D3] regulates mineral and bone homeostasis and exerts potent anti-inflammatory and antiproliferative properties through binding to the vitamin D receptor (VDR). The 3D structures of the VDR ligand-binding domain with 1,25(OH)2D3 or gemini analogs unveiled the molecular mechanism underlying ligand recognition. On the basis of structure-function correlations, we generated a point-mutated VDR (VDR(gem)) that is unresponsive to 1,25(OH)2D3, but the activity of which is efficiently induced by the gemini ligands.

Modulators of vitamin D nuclear receptor: recent advances from structural studies.

The vitamin D nuclear receptor (VDR) and its ligand, 1α, 25-dihydroxyvitamin D3 (1,25(OH)2D3, or calcitriol) regulate numerous biological functions. Therefore, VDR represents an important therapeutic target in the treatment of various diseases such as cancers, psoriasis, rickets, renal osteodystrophy, and autoimmune dysfunctions. Despite the number of newly synthesized 1,25(OH)2D3 analogues, the need for highly potential modulators of VDR with precise cell-, gene- or coregulator-selectivity still exists.

Structural insights into the molecular mechanism of vitamin D receptor activation by lithocholic acid involving a new mode of ligand recognition.

The vitamin D receptor (VDR), an endocrine nuclear receptor for 1α,25-dihydroxyvitamin D3, acts also as a bile acid sensor by binding lithocholic acid (LCA). The crystal structure of the zebrafish VDR ligand binding domain in complex with LCA and the SRC-2 coactivator peptide reveals the binding of two LCA molecules by VDR. One LCA binds to the canonical ligand-binding pocket, and the second one, which is not fully buried, is anchored to a site located on the VDR surface.