Raaijmakers Hans C A, Versteegh Judith E, Uitdehaag Joost C M
Departments of Molecular Design and Informatics, Molecular Pharmacology and DMPK, Schering-Plough Research Institute, P. O. Box 20, 5340 BH Oss, The Netherlands.
J Biol Chem. 2009 Jul 17;284(29):19572-9. doi: 10.1074/jbc.M109.007872. Epub 2009 Apr 16.
Here we describe the 1.95 A structure of the clinically used antiprogestin RU486 (mifepristone) in complex with the progesterone receptor (PR). The structure was obtained by taking a crystal of the PR ligand binding domain containing the agonist norethindrone and soaking it in a solution containing the antagonist RU486 for extended times. Clear ligand exchange could be observed in one copy of the PR ligand binding domain dimer in the crystal. RU486 binds while PR is in an agonistic conformation without displacing helix 12. Although this is probably because of the constraints of the crystal lattice, it demonstrates that helix 12 displacement is not a prerequisite for RU486 binding. Interestingly, B-factor analysis clearly shows that helix 12 becomes more flexible after RU486 binding, suggesting that RU486, being a model antagonist, does not induce one fixed conformation of helix 12 but changes its positional equilibrium. This conclusion is confirmed by comparing the structures of RU486 bound to PR and RU486 bound to the glucocorticoid receptor.
在此，我们描述了临床使用的抗孕激素RU486（米非司酮）与孕激素受体（PR）复合物的1.95埃结构。该结构是通过获取含有激动剂炔诺酮的PR配体结合域晶体，并将其长时间浸泡在含有拮抗剂RU486的溶液中得到的。在晶体中的PR配体结合域二聚体的一个拷贝中可以观察到明显的配体交换。RU486在PR处于激动构象时结合，而不取代螺旋12。虽然这可能是由于晶格的限制，但它表明螺旋12的取代不是RU486结合的先决条件。有趣的是，B因子分析清楚地表明，RU486结合后螺旋12变得更加灵活，这表明作为模型拮抗剂的RU486不会诱导螺旋12形成一种固定构象，而是改变其位置平衡。通过比较与PR结合的RU486和与糖皮质激素受体结合的RU486的结构，证实了这一结论。
