1YAT

IMPROVED CALCINEURIN INHIBITION BY YEAST FKBP12-DRUG COMPLEXES. CRYSTALLOGRAPHIC AND FUNCTIONAL ANALYSIS

1YAT の概要

• エントリーDOI: 10.2210/pdb1yat/pdb
• 分子名称: FK506 BINDING PROTEIN, 8-DEETHYL-8-[BUT-3-ENYL]-ASCOMYCIN (3 entities in total)
• 機能のキーワード: binding protein
• 由来する生物種: Saccharomyces cerevisiae (baker's yeast)
• 細胞内の位置: Cytoplasm: P20081
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 12842.65

構造登録者

Rotonda, J.,Becker, J.W. (登録日: 1993-01-06, 公開日: 1993-10-31, 最終更新日: 2024-02-14)

主引用文献

Rotonda, J.,Burbaum, J.J.,Chan, H.K.,Marcy, A.I.,Becker, J.W.
Improved calcineurin inhibition by yeast FKBP12-drug complexes. Crystallographic and functional analysis.
J.Biol.Chem., 268:7607-7609, 1993

PubMed Abstract: The protein phosphatase calcineurin is the putative target for the immunosuppressive drug FK-506. The enzyme is inhibited by the complex of the drug with its intracellular receptor, the 12-kDa FK-506-binding protein (FKBP12), and the strength of inhibition usually correlates strongly with immunosuppressive potency. We find, however, that the complex of yeast FKBP12 with L-685,818, a well characterized antagonist of FK-506 immunosuppression, is a potent inhibitor of calcineurin. The corresponding human complex does not inhibit the enzyme, and both human and yeast complexes with FK-506 do inhibit. To understand the structural basis of these findings, we have determined the three-dimensional structure of the complex of yeast FKBP12 with FK-506 by x-ray crystallography, and have found that the structure of the yeast complex is strikingly similar to its human homolog. These observations indicate that specific sequence elements in the yeast protein provide stronger binding interactions with a heterologous calcineurin than do the corresponding elements in the human protein, and suggest structural modifications that may improve the potency of this class of immunosuppressants.

PubMed: 7681823

実験手法

X-RAY DIFFRACTION (2.5 Å)