5XPN

Crystal structure of VDR-LBD complexed with 25RS-(hydroxyphenyl)-25-methoxy-2-methylidene-19,26,27-trinor-1-hydroxyvitamin D3

Summary for 5XPN

• Entry DOI: 10.2210/pdb5xpn/pdb
• Descriptor: Vitamin D3 receptor, Mediator of RNA polymerase II transcription subunit 1, (1~{R},3~{R})-5-[(2~{E})-2-[(1~{R},3~{a}~{S},7~{a}~{R})-1-[(2~{R},6~{S})-6-(4-hydroxyphenyl)-6-methoxy-hexan-2-yl]-7~{a}-methyl-2,3,3~{a},5,6,7-hexahydro-1~{H}-inden-4-ylidene]ethylidene]-2-methylidene-cyclohexane-1,3-diol, ... (5 entities in total)
• Functional Keywords: transcription, vitamin d3, vdr, vdre, rxr, co-factors
• Biological source: Rattus norvegicus (Rat); More
• Total number of polymer chains: 2
• Total formula weight: 33155.35

Authors

Kato, A.,Itoh, T.,Yamamoto, K. (deposition date: 2017-06-03, release date: 2018-07-11, Last modification date: 2024-03-27)

Primary citation

Kato, A.,Yamao, M.,Hashihara, Y.,Ishida, H.,Itoh, T.,Yamamoto, K.
Vitamin D Analogues with a p-Hydroxyphenyl Group at the C25 Position: Crystal Structure of Vitamin D Receptor Ligand-Binding Domain Complexed with the Ligand Explains the Mechanism Underlying Full Antagonistic Action
J. Med. Chem., 60:8394-8406, 2017

PubMed Abstract: Vitamin D receptor (VDR) antagonists can be classified into two categories: the first category of VDR antagonists, which do not stabilize the helix 11-12, and the second category of antagonists, which destabilize the helix 6-7 region. To elucidate the mechanism underlying the first category antagonists by using the crystal structure, we designed and synthesized several VDR ligands with a p-hydroxyphenyl group at the C25-position. Of these, 22S-butyl-25-carbonyl analogue 5b and 25-di-p-hydoroxyphenyl analogues 6a,b showed strong antagonistic activity. We succeeded in cocrystallizing the ligand-binding domain of VDR complexed with 5b and found that the structure showed an alternative conformation of the helix 11-12 that explained the mechanism of the first category antagonists. Taking the present and previous studies together, we could elucidate the mechanisms underlying first and second categories antagonists based on individual crystal structures. This study provides significant insights into antagonism against not only VDR but also nuclear receptors.

PubMed: 28954197
DOI: 10.1021/acs.jmedchem.7b00819

Experimental method

X-RAY DIFFRACTION (1.96 Å)