3VRV

VDR ligand binding domain in complex with 2-Methylidene-26,27-dimethyl-19,24-dinor-1alpha,25-dihydroxyvitamin D3

Summary for 3VRV

• Entry DOI: 10.2210/pdb3vrv/pdb
• Related: 3VRT 3VRU 3VRW
• Descriptor: Vitamin D3 receptor, 13-meric peptide from Mediator of RNA polymerase II transcription subunit 1, (1R,3R,7E,17beta)-17-[(2R)-5-ethyl-5-hydroxyheptan-2-yl]-2-methylidene-9,10-secoestra-5,7-diene-1,3-diol, ... (4 entities in total)
• Functional Keywords: nuclear hormone receptor, transcription, vitamin d3, vdre, rxr, co-factors, nuclear
• Biological source: Rattus norvegicus (Rat); More
• Cellular location: Nucleus: P13053 Q15648
• Total number of polymer chains: 2
• Total formula weight: 32596.60

Authors

Yoshimoto, N.,Inaba, Y.,Itoh, T.,Nakabayashi, M.,Ito, N.,Yamamoto, K. (deposition date: 2012-04-14, release date: 2012-05-23, Last modification date: 2024-03-20)

Primary citation

Yoshimoto, N.,Sakamaki, Y.,Haeta, M.,Kato, A.,Inaba, Y.,Itoh, T.,Nakabayashi, M.,Ito, N.,Yamamoto, K.
Butyl pocket formation in the vitamin d receptor strongly affects the agonistic or antagonistic behavior of ligands
J.Med.Chem., 55:4373-4381, 2012

PubMed Abstract: Previously, we reported that 22S-butyl-25,26,27-trinor-1α,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.

PubMed: 22512505
DOI: 10.1021/jm300230a

Experimental method

X-RAY DIFFRACTION (1.9 Å)