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Titolo:
Model of three-dimensional structure of vitamin D receptor and its bindingmechanism with 1 alpha,25-dihydroxyvitamin D-3
Autore:
Rotkiewicz, P; Sicinska, W; Kolinski, A; DeLuca, HF;
Indirizzi:
Univ Wisconsin, Dept Biochem, Madison, WI 53706 USA Univ Wisconsin Madison WI USA 53706 , Dept Biochem, Madison, WI 53706 USA Univ Warsaw, Dept Chem, Warsaw, Poland Univ Warsaw Warsaw PolandUniv Warsaw, Dept Chem, Warsaw, Poland Donald Danforth Plant Sci Ctr, St Louis, MO USA Donald Danforth Plant Sci Ctr St Louis MO USA Sci Ctr, St Louis, MO USA
Titolo Testata:
PROTEINS-STRUCTURE FUNCTION AND GENETICS
fascicolo: 3, volume: 44, anno: 2001,
pagine: 188 - 199
SICI:
0887-3585(20010815)44:3<188:MOTSOV>2.0.ZU;2-T
Fonte:
ISI
Lingua:
ENG
Soggetto:
NUCLEAR-MAGNETIC-RESONANCE; THYROID-HORMONE RECEPTOR; RETINOID-X-RECEPTOR; TRANSCRIPTIONAL ACTIVATION; CRYSTAL-STRUCTURE; CONFORMATIONAL-ANALYSIS; COACTIVATOR INTERACTION; DOMAIN; LIGAND; AFFINITY;
Keywords:
vitamin D receptor; steroid hormone receptor; docking of 1 alpha,25-dihydroxyvitamin D; nuclear receptor; 6-s-trans-1 alpha,25-dihydroxyvitamin D-3;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
62
Recensione:
Indirizzi per estratti:
Indirizzo: DeLuca, HF Univ Wisconsin, Dept Biochem, 433 Babcock Dr, Madison, WI 53706USA Univ Wisconsin 433 Babcock Dr Madison WI USA 53706 WI 53706 USA
Citazione:
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

Abstract

Comparative modeling of the vitamin D receptor three-dimensional structureand computational docking of 1 alpha ,25-dihydroxyvitamin D-3 into the putative binding pocket of the two deletion mutant receptors: (207-423) and (120-422, Delta [164-207]) are reported and evaluated in the context of extensive mutagenic analysis and crystal structure of holo hVDR deletion proteinpublished recently. The obtained molecular model agrees well with the experimentally determined structure. Six different conformers of la,25-dihydroxyvitamin D3 were used to study flexible docking to the receptor. On the basis of values of conformational energy of various complexes and their consistency with functional activity, it appears that la,25-dihydroxyvitamin D3 binds the receptor in its 6-s-trans form. The two lowest energy complexes obtained from docking the hormone into the deletion protein (207-423) differ in conformation of ring A and orientation of the ligand molecule in the VDRpocket. 1 alpha ,25-Dihydroxyvitamin D3 possessing the A-ring conformationwith axially oriented 1 alpha -hydroxy group binds receptor with its 25-hydroxy substituent oriented toward the center of the receptor cavity, whereas ligand possessing equatorial conformation of 1 alpha -hydroxy enters the pocket with A ring directed inward. The latter conformation and orientationof the ligand is consistent with the crystal structure of hVDR deletion mutant (118-425, Delta [165-215]). The lattice model of rVDR (120-422, Delta [164-207]) shows excellent agreement with the crystal structure of the hVDRmutant. The complex obtained from docking the hormone into the receptor has lower energy than complexes for which homology modeling was used. Thus, asimple model of vitamin D receptor with the first two helices deleted can be potentially useful for designing a general structure of ligand, whereas the advanced lattice model is suitable for examining binding sites in the pocket. (C) 2001 Wiley-Liss, Inc.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 30/03/20 alle ore 19:30:56