3VTC

Crystal structure of rat vitamin D receptor bound to a partial agonist 26-adamantyl-23-yne-19-norvitammin D ADTK3

Summary for 3VTC

• Entry DOI: 10.2210/pdb3vtc/pdb
• Related: 2ZLC 3VTB 3VTD
• Descriptor: Vitamin D3 receptor, COACTIVATOR PEPTIDE DRIP, (1R,3R,7E,17beta)-17-{(2R,6R)-6-hydroxy-7-[(3S,5S,7S)-tricyclo[3.3.1.1~3,7~]dec-1-yl]hept-4-yn-2-yl}-2-methylidene-9,10-secoestra-5,7-diene-1,3-diol, ... (5 entities in total)
• Functional Keywords: transcription, hormone receptor
• Biological source: Rattus norvegicus (rats); More
• Cellular location: Nucleus: P13053
• Total number of polymer chains: 2
• Total formula weight: 32760.80

Authors

Nakabayashi, M.,Kudo, T.,Tokiwa, H.,Makishima, M.,Yamada, S.,Ikura, T.,Ito, N. (deposition date: 2012-05-26, release date: 2013-06-12, Last modification date: 2023-11-08)

Primary citation

Kudo, T.,Ishizawa, M.,Maekawa, K.,Nakabayashi, M.,Watarai, Y.,Uchida, H.,Tokiwa, H.,Ikura, T.,Ito, N.,Makishima, M.,Yamada, S.
Combination of Triple Bond and Adamantane Ring on the Vitamin D Side Chain Produced Partial Agonists for Vitamin D Receptor.
J.Med.Chem., 2014

PubMed Abstract: Vitamin D receptor (VDR) ligands are therapeutic agents that are used for the treatment of psoriasis, osteoporosis, and secondary hyperparathyroidism and have immense potential as therapeutic agents for autoimmune diseases, cancers, and cardiovascular diseases. However, the major side effect of VDR ligands, the development of hypercalcemia, limits their expanded use. To develop tissue-selective VDR modulators, we have designed vitamin D analogues with an adamantane ring at the side chain terminal, which would interfere with helix 12, the activation function 2, and modulate the VDR potency. Here we report 25- or 26-adamantyl-23,23,24,24-tetradehydro-19-norvitamin D derivatives (ADTK1-4, 4b,a and 5a,b). These compounds showed high VDR affinities (90% at maximum), partial agonistic activities (EC50 10(-9)-10(-8) M with 40-80% efficacy) in transactivation, and tissue-selective activity in target gene expressions. We investigate the structure-activity relationships of these compounds on the basis of their X-ray crystal structures.

PubMed: 24773565
DOI: 10.1021/jm401989c

Experimental method

X-RAY DIFFRACTION (1.5 Å)