Vitamin D Nuclear Receptor
This Jmol Exploration was created using the Jmol Exploration Webpage Creator from the MSOE Center for BioMolecular Modeling.
This family of proteins is primarily responsible for the binding of steroid hormones, thyroid and other endocrine hormones, and certain other metabolites and ligands. Nuclear receptors also have the ability to bind directly to DNA and regulate the expression of some genes. The vitamin D receptor falls into this category because it is capable of binding vitamin D in its ligand binding domain, as well as binding to DNA in its DNA binding domain.
Structure OverviewThe Vitamin D receptor is capable of binding the vitamin D ligand. Vitamin D is fat soluble and important for bone health, innate immune system activation, and the prevention of some cancers. Humans obtain vitamin D through sun exposure, certain foods, and dietary supplements. This is the inert form of the vitamin. Vitamin D becomes biologically active when two additional hydroxyl groups are added. The first hydroxylation occurs in the liver when vitamin D is converted to calcidiol (25-hydroxyvitamin D), and the second occurs in the kidneys and forms calcitriol (1,25-dihydroxyvitamin D). The fully activated form of vitamin D can function as a hormone.
When released by the kidneys, it can act on intestinal cells in the duodenum and control the amount of Calcium that is absorbed through the diet. It does this by regulating active transport of Calcium across the intestinal epithelium and by encouraging the synthesis of a Calcium transport protein called calbindin. It can also control levels of serum Calcium and the formation of the skeleton by activating bone cell remodeling of osteoblasts and osteoclasts. Through its impact on Calcium, vitamin D also helps to regulate neuromuscular function, cell growth and proliferation, and immune function. An inadequate level of active vitamin D in the body can lead to health complications such as rickets in children and osteoporosis in adults.
Rickets is the softening and weakening of bones in children as a direct result of vitamin D deficiency and the bodys inability to regulate Calcium uptake levels. Symptoms of this disease include delayed growth, muscle weakness, and joint pain. Characteristic skeletal deformities can also form in the wrists, ankles, and breastbone, as well as bowed legs. Risk factors include living in northern latitudes with less sunlight in the winter months, having darker skin (which does not react with sunlight as readily), and being between 3 and 36 months of age (since the skeleton grows so rapidly and uses a lot of Calcium that needs to be replenished during this time). Vitamin D levels can be increased by encouraging children to spend more time outdoors and to eat foods that are rich in this nutrient, such as fish and egg yolks. Rickets can develop as a complication of other disorders that affect Calcium uptake, such as Celiac Disease and Inflammatory Bowel Disease.
Bones are in a constant state of being renewed. Osteoporosis occurs when the creation of new bone does not keep up wit the degradation and removal of old bone structure. This causes the bones to be weak, frail, and fracture more easily. Signs of severely weakened bones in adults include loss of height, a stooped posture, and back pain caused by damaged vertebrae. Low levels of vitamin D and Calcium absorption can lead directly to osteoporosis as a complication.
The vitamin D receptor has a DNA binding domain that can attach to certain sequences of DNA, and this allows vitamin D to act as a transcription factor for some genes. The vitamin D receptor binds as a retinoid x receptor (RXR) heterodimer to regulatory sequences near target gene sites. Once the receptor has bound, vitamin D can regulate transcription by recruiting cofactors, modifying histones, repositioning nucleosomes, and recruiting RNA polymerase II. Genes for osteocalcin (Bglap), osteoponin (Spp1), and the vitamin D receptor itself (VDR) are known to be regulated in this fashion.
Secondary Structure:
The vitamin D receptor contains 3 short beta sheets that cover 7 amino acid residues. These form a beta meander super-secondary structure.
The vitamin D receptor contains 15 separate alpha helix segments that cover a large portion of the molecules structure (167 amino acid residues). The alpha helices are stabilized by hydrogen bonding attractive forces along the backbone.
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Tertiary Structure:
The tertiary structure of vitamin D is formed by interactions among the amino acid side chains in the single monomer. These interactions allow to molecule to fold in such a way that several critical functional domains are formed; the ligand binding domain, the DNA binding domain, and the heterodimerization domain.
Alpha helix 12 (H12) is the most critical point within the molecules ligand binding domain for vitamin D. It is positioned ideally to form the initial hydrophobic interactions with vitamin D, which is itself very nonpolar. These hydrophobic interactions occur at Val-418 and Phe-422 and interact directly with vitamin Ds methyl groups. His-397 and Tyr-401 are hydrophilic interactions that help to stabilize the position of H12 while also interacting with the ligand.
The following amino acid residues interact directly with the Vitamin D ligand:
Tyrosine 143
From Helix 3:
Leucine 227
Leucine 233
Valine 234
Serine 237
From Helix 5:
Arginine 274
Serine 275
Serine 278
From Beta Sheet 2:
Tryptophan 286
Cysteine 288
Histidine 305
From Helix 11:
Histidine 397
All 3 beta sheets also have amino acid residues that interact with the vitamin D ligand, which helps to increase the vitamin D receptors overall binding capacity. For example, the beta 1 strand helps to position the ligand correctly with its Trp-286 residue.
Helix 12 and Beta sheets - Interacting ResiduesAfter being activated by vitamin D, the vitamin D receptor forms a heterodimer with the retinoid X receptor. The retinoid X receptor is a type 2 nuclear receptor that can heterodimerize with type 1 nuclear receptors, like the VDR. When the ligand binds, transcription corepressors disassociate and coactivator proteins are recruited to promote transcription. The new heterodimer can bind to hormone response elements on DNA and control expression or suppression of transcription. Hormone response elements are short sequences of DNA within the promoter of a gene that can bind to receptors that regulate transcription. The VDR and RXR together make up the DNA binding domain.
The VDR and RXR are rotated at a 45 degree angle (relative to each other) around the DNA helix, with the RXR positioned on the 5 end and the VDR positioned on the 3 end. The domain sequence MEAMAASTSLPDPGDFD could provide specific base pair interactions with the DNA itself, most likely with Ser/Thr, Glu/Asp, and Phe interactions.
Orlov, I., Rochel, N., Moras, D., Klaholz, B. (2011). Structure of the full human RXR/VDR nuclear receptor heterodimer complex with its DR3 target DNA. The EMBO Journal, 31: 291-300. doi: 10.1038/emboj.2011.445. Retrieved from http://www.nature.com/emboj/journal/v31/n2/full/emboj2011445a.html
Pike, W., Meyer, M., Martowicz, M., Bishop, K., Lee, S., Nerenz, R., Goetsch, P. (2010). Emerging regulatory paradigms for control of gene expression by 1,25-dihydroxyvitamin D3. Journal of Steroid Biochemistry and Molecular Biology, 121: 130-135. doi: 10.1016/j.jsbmb.2010.02.036. Retrieved from ScienceDirect.
Heaney, R. (2008). Vitamin D and calcium interactions: functional outcomes 1,2,3, and 4. The American Journal of Clinical Nutrition, 88(2): 5415-5445. Retrieved from http://ajcn.nutrition.org/content/88/2/541S.full
National Institutes of Health (2013). Dietary Supplement Fact Sheet: Vitamin D. Office of Dietary Supplements. Retrieved from http://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/#h7
Goodsell, D., Protein Data Bank (2012). Molecule of the Month: Vitamin D Receptor. Retrieved from http://www.pdb.org/pdb/101/motm.do?momID=155
The Mayo Clinic (2013). Osteoporosis. Retrieved from
http://www.mayoclinic.com/health/osteoporosis/DS00128/DSECTION=risk-factors
The Mayo Clinic (2013). Rickets. Retrieved from
http://www.mayoclinic.com/health/rickets/DS00813/DSECTION=risk-factors