3VRW: Vdr Ligand Binding Domain In Complex With 22s-Butyl-2-Methylidene-26, 27-Dimethyl-19,24-Dinor-1alpha,25-Dihydroxyvitamin D3

Citation:
Abstract
Previously, we reported that 22S-butyl-25,26,27-trinor-1alpha,24-dihydroxyvitamin D(3)2 represents a new class of antagonist for the vitamin D receptor (VDR). The crystal structure of the ligand-binding domain (LBD) of VDR complexed with 2 showed the formation of a butyl pocket to accommodate the 22-butyl group and insufficient interactions between ligand 2 and the C-terminus of VDR. Here, we designed and synthesized new analogues 5a-c and evaluated their biological activities to probe whether agonistic activity is recovered when the analogue restores interactions with the C-terminus of VDR. Analogues 5a-c exhibited full agonistic activity in transactivation. Interestingly, 5c, which bears a 24-diethyl group, completely recovered agonistic activity, although 3c and 4c act as an antagonist and a weak agonist, respectively. The crystal structures of VDR-LBD complexed with 3a, 4a, 5a, and 5c were solved, and the results confirmed that butyl pocket formation in VDR strongly affects the agonistic or antagonistic behaviors of ligands.
PDB ID: 3VRWDownload
MMDB ID: 99884
PDB Deposition Date: 2012/4/16
Updated in MMDB: 2012/05
Experimental Method:
x-ray diffraction
Resolution: 2.4  Å
Source Organism:
Rattus norvegicus
Similar Structures:
Biological Unit for 3VRW: dimeric; determined by author and by software (PISA)
Molecular Components in 3VRW
Label Count Molecule
Proteins (2 molecules)
1
Vitamin D3 Receptor(Gene symbol: Vdr)
Molecule annotation
1
13-meric Peptide From Mediator of RNA Polymerase II Transcription Subunit 1(Gene symbol: MED1)
Molecule annotation
Chemical (1 molecule)
1
1
* Click molecule labels to explore molecular sequence information.

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