5XZF

Vitamin D receptor with a synthetic ligand ADRO1

Summary for 5XZF

• Entry DOI: 10.2210/pdb5xzf/pdb
• Descriptor: Vitamin D3 receptor, Mediator of RNA polymerase II transcription subunit 1, (1R,3S,5Z)-5-[(2E)-2-[(1R,3aS,7aR)-1-[(2R,6S)-6-(1-adamantyl)-6-oxidanyl-hex-4-yn-2-yl]-7a-methyl-2,3,3a,5,6,7-hexahydro-1H-inden-4-ylidene]ethylidene]-4-methylidene-cyclohexane-1,3-diol, ... (5 entities in total)
• Functional Keywords: vitamin d receptor, vitamin d analogue, adamantan, transcription
• Biological source: Rattus norvegicus (Rat); More
• Total number of polymer chains: 2
• Total formula weight: 32730.73

Authors

Otero, R.,Numoto, N.,Ikura, T.,Yamada, S.,Mourino, A.,Makishima, M.,Ito, N. (deposition date: 2017-07-12, release date: 2018-07-25, Last modification date: 2023-11-22)

Primary citation

Otero, R.,Ishizawa, M.,Numoto, N.,Ikura, T.,Ito, N.,Tokiwa, H.,Mourino, A.,Makishima, M.,Yamada, S.
25 S-Adamantyl-23-yne-26,27-dinor-1 alpha ,25-dihydroxyvitamin D3: Synthesis, Tissue Selective Biological Activities, and X-ray Crystal Structural Analysis of Its Vitamin D Receptor Complex.
J. Med. Chem., 61:6658-6673, 2018

PubMed Abstract: Both 25 R- and 25 S-25-adamantyl-23-yne-26,27-dinor-1α,25-dihydroxyvitamin D (4a and 4b) were stereoselectively synthesized by a Pd(0)-catalyzed ring closure and Suzuki-Miyaura coupling between enol-triflate 7 and alkenyl-boronic ester 8. The 25 S isomer (4b) showed high vitamin D receptor (VDR) affinity (50% of that of the natural hormone 1α,25-dihydroxyvitamin D, 1) and transactivation potency (kidney HEK293, 90%). In endogenous gene expression, it showed high cell-type selectivity for kidney cells (HEK293, CYP24A1 160% of 1), bone cells (MG63, osteocalcin 64%), and monocytes (U937, CAMP 96%) over intestine (SW480, CYP24A1 8%) and skin (HaCaT, CYP24A1 7%) cells. The X-ray crystal structural analysis of 4b in complex with rat VDR-ligand binding domain (LBD) showed the highest Cα positional shift from the 1/VDR-LBD complex at helix 11. Helix 11 of the 4b and 1 VDR-LBD complexes also showed significant differences in surface properties. These results suggest that 4b should be examined further as another candidate for a mild preventive osteoporosis agent.

PubMed: 29989817
DOI: 10.1021/acs.jmedchem.8b00427

Experimental method

X-RAY DIFFRACTION (2.1 Å)