2ZXN

A New Class of Vitamin D Receptor Ligands that Induce Structural Rearrangement of the Ligand-binding Pocket

Summary for 2ZXN

• Entry DOI: 10.2210/pdb2zxn/pdb
• Related: 2ZXM
• Descriptor: Vitamin D3 receptor, Mediator of RNA polymerase II transcription subunit 1, (1R,3S,5Z)-5-[(2E)-2-[(1R,3aS,7aR)-1-[(2S,3S)-3-(2-hydroxyethyl)heptan-2-yl]-7a-methyl-2,3,3a,5,6,7-hexahydro-1H-inden-4-ylidene]ethylidene]-4-methylidene-cyclohexane-1,3-diol, ... (4 entities in total)
• Functional Keywords: nuclear receptor-agonist complex, transcription, dna-binding, metal-binding, nucleus, phosphoprotein, receptor, transcription regulation, zinc, zinc-finger, activator
• Biological source: Rattus norvegicus (rat); More
• Cellular location: Nucleus: P13053; Nucleus (By similarity): A1L0Z0
• Total number of polymer chains: 2
• Total formula weight: 32596.60

Authors

Nakabayashi, M.,Ikura, T.,Ito, N. (deposition date: 2009-01-04, release date: 2009-02-17, Last modification date: 2023-11-01)

Primary citation

Inaba, Y.,Yoshimoto, N.,Sakamaki, Y.,Nakabayashi, M.,Ikura, T.,Tamamura, H.,Ito, N.,Shimizu, M.,Yamamoto, K.
A New Class of Vitamin D Analogues that Induce Structural Rearrangement of the Ligand-Binding Pocket of the Receptor
J.Med.Chem., 52:1438-1449, 2009

PubMed Abstract: To identify novel vitamin D receptor (VDR) ligands that induce a novel architecture within the ligand-binding pocket (LBP), we have investigated eight 22-butyl-1alpha,24-dihydroxyvitamin D(3) derivatives (3-10), all having a butyl group as the branched alkyl side chain. We found that the 22S-butyl-20-epi-25,26,27-trinorvitamin D derivative 5 was a potent VDR agonist, whereas the corresponding compound 4 with the natural configuration at C(20) was a potent VDR antagonist. Analogues with the full vitamin D(3) side chain were less potent agonist, and whether they were agonists or antagonists depended on the 24-configuration. X-ray crystal structures demonstrated that the VDR-LBD accommodating the potent agonist 5 has an architecture wherein the lower side and the helix 11 side of the LBP is simply expanded relative to the canonical active-VDR situation; in contrast, the potent antagonist 4 induces an extra cavity to accommodate the branched moiety. This is the first report of a VDR antagonist that generates a new cavity to alter the canonical pocket structure of the ligand occupied VDR.

PubMed: 19193059
DOI: 10.1021/jm8014348

Experimental method

X-RAY DIFFRACTION (2.1 Å)