3A40

Crystal structure of the human VDR ligand binding domain bound to the synthetic agonist compound 2alpha-methyl-AMCR277B(C23R)

Summary for 3A40

• Entry DOI: 10.2210/pdb3a40/pdb
• Related: 1DB1 2HB8 3A3Z 3CS6
• Descriptor: Vitamin D3 receptor, (1S,2S,3R,5Z,7E,14beta,17alpha,23R)-23-(2-hydroxy-2-methylpropyl)-2-methyl-20,24-epoxy-9,10-secochola-5,7,10-triene-1,3-diol, SULFATE ION, ... (4 entities in total)
• Functional Keywords: transcription, structural genomics, spine2, structural proteomics in europe 2, gene regulation, spine-2
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: P11473
• Total number of polymer chains: 1
• Total formula weight: 30456.14

Authors

Sato, Y.,Antony, P.,Huet, T.,Sigueiro, R.,Rochel, N.,Moras, D.,Structural Proteomics in Europe 2 (SPINE-2) (deposition date: 2009-06-25, release date: 2010-02-02, Last modification date: 2023-11-01)

Primary citation

Antony, P.,Sigueiro, R.,Huet, T.,Sato, Y.,Ramalanjaona, N.,Rodrigues, L.C.,Mourino, A.,Moras, D.,Rochel, N.
Structure-function relationships and crystal structures of the vitamin D receptor bound 2 alpha-methyl-(20S,23S)- and 2 alpha-methyl-(20S,23R)-epoxymethano-1 alpha,25-dihydroxyvitamin D3
J.Med.Chem., 53:1159-1171, 2010

PubMed Abstract: The vitamin D nuclear receptor is a ligand-dependent transcription factor that controls multiple biological responses such as cell proliferation, immune responses, and bone mineralization. Numerous 1 alpha,25(OH)(2)D(3) analogues, which exhibit low calcemic side effects and/or antitumoral properties, have been synthesized. We recently showed that the synthetic analogue (20S,23S)-epoxymethano-1 alpha,25-dihydroxyvitamin D(3) (2a) acts as a 1 alpha,25(OH)(2)D(3) superagonist and exhibits both antiproliferative and prodifferentiating properties in vitro. Using this information and on the basis of the crystal structures of human VDR ligand binding domain (hVDR LBD) bound to 1 alpha,25(OH)(2)D(3), 2 alpha-methyl-1 alpha,25(OH)(2)D(3), or 2a, we designed a novel analogue, 2 alpha-methyl-(20S,23S)-epoxymethano-1 alpha,25-dihydroxyvitamin D(3) (4a), in order to increase its transactivation potency. Here, we solved the crystal structures of the hVDR LBD in complex with the 4a (C23S) and its epimer 4b (C23R) and determined their correlation with specific biological outcomes.

PubMed: 20070104
DOI: 10.1021/jm9014636

Experimental method

X-RAY DIFFRACTION (1.45 Å)