3W5T

Crystal structure of complexes of vitamin D receptor ligand binding domain with lithocholic acid derivatives

Summary for 3W5T

• Entry DOI: 10.2210/pdb3w5t/pdb
• Related: 3W5P 3W5Q 3W5R
• Descriptor: Vitamin D3 receptor, Mediator of RNA polymerase II transcription subunit 1, (3beta,5beta,9beta)-3-(propanoyloxy)cholan-24-oic acid, ... (4 entities in total)
• Functional Keywords: zinc-finger, nuclear receptor-agonist complex, transcription, receptor, transcription regulation, activator, dna-binding, metal-binding, phosphoprotein, nucleus
• Biological source: Rattus norvegicus (rat); More
• Cellular location: Nucleus: P13053 Q15648
• Total number of polymer chains: 2
• Total formula weight: 32598.57

Authors

Masuno, H.,Ikura, T.,Ito, N. (deposition date: 2013-02-06, release date: 2013-06-26, Last modification date: 2023-11-08)

Primary citation

Masuno, H.,Ikura, T.,Morizono, D.,Orita, I.,Yamada, S.,Shimizu, M.,Ito, N.
Crystal structures of complexes of vitamin D receptor ligand-binding domain with lithocholic acid derivatives.
J.Lipid Res., 54:2206-2213, 2013

PubMed Abstract: The secondary bile acid lithocholic acid (LCA) and its derivatives act as selective modulators of the vitamin D receptor (VDR), although their structures fundamentally differ from that of the natural hormone 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3)]. Here, we have determined the crystal structures of the ligand-binding domain of rat VDR (VDR-LBD) in ternary complexes with a synthetic partial peptide of the coactivator MED1 (mediator of RNA polymerase II transcription subunit 1) and four ligands, LCA, 3-keto LCA, LCA acetate, and LCA propionate, with the goal of elucidating their agonistic mechanism. LCA and its derivatives bind to the same ligand-binding pocket (LBP) of VDR-LBD that 1,25(OH)2D3 binds to, but in the opposite orientation; their A-ring is positioned at the top of the LBP, whereas their acyclic tail is located at the bottom of the LBP. However, most of the hydrophobic and hydrophilic interactions observed in the complex with 1,25(OH)2D3 are reproduced in the complexes with LCA and its derivatives. Additional interactions between VDR-LBD and the C-3 substituents of the A-ring are also observed in the complexes with LCA and its derivatives. These may result in the observed difference in the potency among the LCA-type ligands.

PubMed: 23723390
DOI: 10.1194/jlr.M038307

Experimental method

X-RAY DIFFRACTION (2.29 Å)