Peräkylä Mikael, Molnár Ferdinand, Carlberg Carsten
Department of Chemistry, University of Kuopio, FIN-70211 Kuopio, Finland.
Chem Biol. 2004 Aug;11(8):1147-56. doi: 10.1016/j.chembiol.2004.05.023.
The 26,23-lactone derivative of 1alpha,25-dihydroxyvitamin D3, TEI-9647, is a partial antagonist of the of human vitamin D receptor (VDR). However, we found that TEI-9647 in rat cells behaves as a weak VDR agonist. This behavior could be mimicked in human cells by the double mutagenesis of human VDR (specifically C403S and C410N). The increased agonistic action of TEI-9647 correlates to a gain in the interaction of the VDR with coactivator protein and a decreased stabilization of the antagonistic conformation of the receptor. Molecular dynamics simulations indicated that TEI-9647 acts as antagonist of human VDR by reducing the stability of helix 12 of the ligand binding domain. In contrast, N410 of the rat VDR stabilized, via backbone contacts, the interaction between helices 11 and 12. This results in TEI-9647 becoming a weak agonist in this organism.
1α,25 - 二羟基维生素D3的26,23 - 内酯衍生物TEI - 9647是人类维生素D受体（VDR）的部分拮抗剂。然而，我们发现TEI - 9647在大鼠细胞中表现为弱VDR激动剂。这种行为在人类细胞中可通过人类VDR的双重诱变（具体为C403S和C410N）来模拟。TEI - 9647激动作用的增强与VDR与共激活蛋白相互作用的增加以及受体拮抗构象稳定性的降低相关。分子动力学模拟表明，TEI - 9647通过降低配体结合域螺旋12的稳定性来充当人类VDR的拮抗剂。相比之下，大鼠VDR的N410通过主链接触稳定了螺旋11和12之间的相互作用。这导致TEI - 9647在该生物体中成为弱激动剂。
