@article {295, title = {Computational analysis of the active sites in binary and ternary complexes of the vitamin D receptor}, journal = {The Journal of Steroid Biochemistry and Molecular Biology}, volume = {103}, year = {2007}, month = {2007 Mar}, pages = {305-9}, abstract = {We have developed a program CCOMP that compares overlapping fragments of two protein complexes and identifies differently oriented amino acids. CCOMP initially performs a sequence alignment of the analyzed receptors, then superimposes the corresponding aligned residues, and finally calculates the root mean square deviation (RMSD) of individual atoms, every amino acid and the entire complex. Thus, amino acids important for functional differences between both complexes can be detected. Application of CCOMP to 1alpha,25-(OH)(2)D(3)-hVDR (1DB1) [Proc. Natl. Acad. Sci. U.S.A. 98 (2001) 5491] and 1alpha,25-(OH)(2)D(3)-rVDR-peptide (1RK3) [Biochemistry 43 (2004) 4101] complexes revealed that the peptide (KNHPMLMNLLKDN) mimicking a co-activator sequence significantly changes the side chain conformation of 35 amino acids. Four of these residues (K242, I256, K260, E416) actually contact the peptide, but all of them are essential for biological activity. Only two (L309 and L400) of the 35 differently oriented amino acids contact the ligand. Interestingly, when the peptide is present (1RK3) leucine 400 shifts closer (0.7A) to the vitamin D 26-methyl group. Applying the CCOMP and DSSP programs to binary and ternary VDR complexes also resulted in establishing that seven amino acids (I238, S252, I256, L413, L415, E416, V417) exhibit significant differences in solvent accessibility and are capable of interacting with co-activators.}, keywords = {Binding Sites, Biomimetic Materials, Computer Simulation, Models, Molecular, Peptides, Protein Binding, Protein Structure, Tertiary, Receptors, Calcitriol, Solvents}, issn = {0960-0760}, doi = {10.1016/j.jsbmb.2006.12.077}, author = {Wanda Sicinska and Piotr Rotkiewicz} } @article {298, title = {Model of three-dimensional structure of VDR bound with Vitamin D3 analogs substituted at carbon-2}, journal = {The Journal of Steroid Biochemistry and Molecular Biology}, volume = {89-90}, year = {2004}, month = {2004 May}, pages = {107-10}, 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, might influence interaction with co-modulators involved in calcium homeostasis.}, keywords = {Animals, Calcium, Carbon, Cholecalciferol, Ligands, Models, Molecular, Molecular Conformation, Rats, Receptors, Calcitriol}, issn = {0960-0760}, doi = {10.1016/j.jsbmb.2004.03.102}, author = {Wanda Sicinska and Piotr Rotkiewicz and Hector F. DeLuca} } @article {290, title = {2-Ethyl and 2-ethylidene analogues of 1alpha,25-dihydroxy-19-norvitamin D(3): synthesis, conformational analysis, biological activities, and docking to the modeled rVDR ligand binding domain.}, journal = {Journal of Medicinal Chemistry}, volume = {45}, year = {2002}, month = {2002 Aug 1}, pages = {3366-80}, abstract = {Novel 19-nor analogues of 1alpha,25-dihydroxyvitamin D(3) were prepared and substituted at C-2 with an ethylidene group. The synthetic pathway was via Wittig-Horner coupling of the corresponding A-ring phosphine oxides with the protected 25-hydroxy Grundmann{\textquoteright}s ketones. Selective catalytic hydrogenation of 2-ethylidene analogues provided the 2alpha- and 2beta-ethyl compounds. The 2-ethylidene-19-nor compounds with a methyl group from the ethylidene moiety in a trans relationship to the C(6)-C(7) bond (E-isomers) were more potent than the corresponding Z-isomers and the natural hormone in binding to the vitamin D receptor. Both geometrical isomers (E and Z) of (20S)-2-ethylidene-19-norvitamin D(3) and both 2alpha-ethyl-19-norvitamins (in the 20R- and 20S-series) have much higher HL-60 differentiation activity than does 1alpha,25-(OH)(2)D(3). Both E-isomers (20R and 20S) of 2-ethylidene vitamins are characterized by very high calcemic activity in rats. The three-dimensional structure model of the rat vitamin D receptor and the computational docking of four synthesized (20R)-19-norvitamin D(3) analogues into its binding pocket are also reported.}, keywords = {Animals, Binding Sites, Biological Transport, Calcitriol, Calcium, Cell Differentiation, Chromatography, High Pressure Liquid, HL-60 Cells, Humans, Intestinal Mucosa, Ligands, Magnetic Resonance Spectroscopy, Male, Models, Molecular, Molecular Conformation, Rats, Receptors, Calcitriol, Spectrophotometry, Ultraviolet, Structure-Activity Relationship, Swine}, issn = {0022-2623}, author = {Rafal R. Sicinski and Piotr Rotkiewicz and Andrzej Koli{\'n}ski and Wanda Sicinska and Jean M. Prahl and Connie M. Smith and Hector F. DeLuca} }