Model of three-dimensional structure of VDR bound with Vitamin D3 analogs substituted at carbon-2

The Journal of Steroid Biochemistry and Molecular Biology
W SicinskaHector F DeLuca

Abstract

All Vitamin D analogs possessing the A ring modified at C-2 and showing calcemic activities nest themselves in the VDR binding pocket, oriented towards Tyr 143. Such topology resembles the position of the Vitamin D hormone in hVDRmt [Proc. Natl. Acad. Sci. U.S.A. 98 (2001) 5491]. Conversely, inactive 2beta-methyl-19-nor-analogs anchor the receptor cavity in a distinguishably different manner, namely by their side chain. Moreover, these inactive vitamins have a different conformation around C(6)-C(7) bond. Topology of modeled complexes suggests that a Vitamin D analog will be biologically active if its intercyclic 5,7-diene moiety assumes parallel position to tryptophan aromatic rings; such orientation allows for creating pi-pi interactions. The broad comparison of calcemic activities of the analogs, and their interactions with VDR, revealed that specific hydrophobic contacts are involved in bone calcium mobilization (BCM). These contacts occur between 21-methyl group and a few amino acids (V296, L305 and L309), conserved in the nuclear receptor superfamily. In the inactive 2beta-methyl-19-nor analogs such contacts do not exist. We speculate that two hydrophobic receptor patches, being in close contact with ligand methyl groups,...Continue Reading

References

May 10, 2001·Proceedings of the National Academy of Sciences of the United States of America·G Tocchini-ValentiniD Moras
Nov 9, 2002·Medicinal Research Reviews·Sachiko YamadaKeiko Yamamoto

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Citations

Mar 23, 2005·Bioorganic & Medicinal Chemistry·Gary H PosnerThomas W Kensler
Jan 24, 2007·The Journal of Steroid Biochemistry and Molecular Biology·Mateusz Kurcinski, Andrzej Kolinski
Apr 20, 2010·The Journal of Steroid Biochemistry and Molecular Biology·Mateusz Kurcinski, Andrzej Kolinski
Sep 1, 2005·Proteins·Wanda SicinskaHector F DeLuca

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