4DRH

Co-crystal structure of the PPIase domain of FKBP51, Rapamycin and the FRB fragment of mTOR at low pH

4DRH の概要

• エントリーDOI: 10.2210/pdb4drh/pdb
• 関連するPDBエントリー: 4DRI 4DRJ
• 分子名称: Peptidyl-prolyl cis-trans isomerase FKBP5, Serine/threonine-protein kinase mTOR, RAPAMYCIN IMMUNOSUPPRESSANT DRUG, ... (5 entities in total)
• 機能のキーワード: fk-506 binding domain, hsp90 cochaperone, immunophilin, peptidyl-prolyl isomerase, mammalian target of rapamycin, kinase, signalling, immunosuppression, cancer, isomerase-transferase complex, isomerase/transferase
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Cytoplasm: Q13451; Endoplasmic reticulum membrane; Peripheral membrane protein; Cytoplasmic side: P42345
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 58728.08

構造登録者

Maerz, A.M.,Bracher, A.,Hausch, F. (登録日: 2012-02-17, 公開日: 2013-02-06, 最終更新日: 2023-09-13)

主引用文献

Marz, A.M.,Fabian, A.K.,Kozany, C.,Bracher, A.,Hausch, F.
Large FK506-Binding Proteins Shape the Pharmacology of Rapamycin.
Mol.Cell.Biol., 33:1357-1367, 2013

PubMed Abstract: The immunosuppressant and anticancer drug rapamycin works by inducing inhibitory protein complexes with the kinase mTOR, an important regulator of growth and proliferation. The obligatory accessory partner of rapamycin is believed to be FK506-binding protein 12 (FKBP12). Here we show that rapamycin complexes of larger FKBP family members can tightly bind to mTOR and potently inhibit its kinase activity. Cocrystal structures with FKBP51 and FKBP52 reveal the modified molecular binding mode of these alternative ternary complexes in detail. In cellular model systems, FKBP12 can be functionally replaced by larger FKBPs. When the rapamycin dosage is limiting, mTOR inhibition of S6K phosphorylation can be enhanced by FKBP51 overexpression in mammalian cells, whereas FKBP12 is dispensable. FKBP51 could also enable the rapamycin-induced hyperphosphorylation of Akt, which depended on higher FKBP levels than rapamycin-induced inhibition of S6K phosphorylation. These insights provide a mechanistic rationale for preferential mTOR inhibition in specific cell or tissue types by engaging specific FKBP homologs.

PubMed: 23358420
DOI: 10.1128/MCB.00678-12

実験手法

X-RAY DIFFRACTION (2.3 Å)