Model of three-dimensional structure of vitamin D receptor and its bindingmechanism with 1 alpha,25-dihydroxyvitamin D-3

Rotkiewicz, P Sicinska, W Kolinski, A DeLuca, HF

P. Rotkiewicz et al., Model of three-dimensional structure of vitamin D receptor and its bindingmechanism with 1 alpha,25-dihydroxyvitamin D-3, PROTEINS, 44(3), 2001, pp. 188-199

62

INGLESE

Article

Biochemistry & Biophysics

PROTEINS-STRUCTURE FUNCTION AND GENETICS

0887-3585 → ACNP

44

3

2001

188 - 199

ISI

0887-3585(20010815)44:3<188:MOTSOV>2.0.ZU;2-T

Comparative modeling of the vitamin D receptor three-dimensional structure and computational docking of 1 alpha ,25-dihydroxyvitamin D-3 into the puta tive binding pocket of the two deletion mutant receptors: (207-423) and (12 0-422, Delta [164-207]) are reported and evaluated in the context of extens ive mutagenic analysis and crystal structure of holo hVDR deletion protein published recently. The obtained molecular model agrees well with the exper imentally determined structure. Six different conformers of la,25-dihydroxy vitamin D3 were used to study flexible docking to the receptor. On the basi s of values of conformational energy of various complexes and their consist ency with functional activity, it appears that la,25-dihydroxyvitamin D3 bi nds the receptor in its 6-s-trans form. The two lowest energy complexes obt ained from docking the hormone into the deletion protein (207-423) differ i n conformation of ring A and orientation of the ligand molecule in the VDR pocket. 1 alpha ,25-Dihydroxyvitamin D3 possessing the A-ring conformation with axially oriented 1 alpha -hydroxy group binds receptor with its 25-hyd roxy substituent oriented toward the center of the receptor cavity, whereas ligand possessing equatorial conformation of 1 alpha -hydroxy enters the p ocket with A ring directed inward. The latter conformation and orientation of the ligand is consistent with the crystal structure of hVDR deletion mut ant (118-425, Delta [165-215]). The lattice model of rVDR (120-422, Delta [ 164-207]) shows excellent agreement with the crystal structure of the hVDR mutant. The complex obtained from docking the hormone into the receptor has lower energy than complexes for which homology modeling was used. Thus, a simple model of vitamin D receptor with the first two helices deleted can b e potentially useful for designing a general structure of ligand, whereas t he advanced lattice model is suitable for examining binding sites in the po cket. (C) 2001 Wiley-Liss, Inc.