TY - JOUR T1 - Structural changes of vitamin D receptor induced by 20-epi-1alpha,25-(OH)2D3: an insight from a computational analysis JF - The Journal of Steroid Biochemistry and Molecular Biology Y1 - 2009 A1 - Wanda Sicinska A1 - Piotr Rotkiewicz KW - Animals KW - Bone Density Conservation Agents KW - Calcitriol KW - Computer Simulation KW - Crystallography, X-Ray KW - Drug Design KW - Humans KW - Ligands KW - Molecular Structure KW - Protein Structure, Tertiary KW - Receptors, Calcitriol KW - Reproducibility of Results KW - Software KW - Transcription, Genetic AB - We employ a new computational tool CCOMP for the comparison of side chain (SC) conformations between crystal structures of homologous protein complexes. The program is applied to the vitamin D receptor (VDR) liganded with 1alpha,25-(OH)(2)D(3) (in 1DB1) or its 20-epi (in 1IE9) analog with an inverted C-20 configuration. This modification yields no detectable changes in the backbone configuration or ligand topology in the receptor binding cavity, yet it dramatically increases transcription, differentiation and antiproliferation activity of the VDR. We applied very stringent criteria during the comparison process. To eliminate errors arising from the different packing of investigated crystals and the thermal flexibility of atoms, we studied complexes belonging to the same space group, having a low R value (0.2) and a B-factor below 40 for compared residues. We find that 20-epi-1alpha,25-(OH)(2)D(3) changes side chain conformation of amino acids residing far away from direct ligand-VDR contacts. We further verify that a number of the reoriented residues were identified in mutational experiments as important for interaction with SRC-1, GRIP, TAFs co-activators and VDR-RXR heterodimerization. Thus, CCOMP analysis of protein complexes may be used for identifying amino acids that could serve as targets for genetic engineering, such as mutagenesis. VL - 113 IS - 3-5 ER -