9EY3

The FK1 domain of FKBP51 in complex with (3S,11S,11aS)-12-((3,5-dichlorophenyl)sulfonyl)-5-oxo-11-vinyldecahydro-1H-6,10-epiminopyrrolo[1,2-a]azonine-3-carboxylic acid

これはPDB形式変換不可エントリーです。

9EY3 の概要

• エントリーDOI: 10.2210/pdb9ey3/pdb
• 分子名称: Peptidyl-prolyl cis-trans isomerase FKBP5, (1~{S},4~{S},7~{S},8~{S},9~{R})-13-[3,5-bis(chloranyl)phenyl]sulfonyl-8-ethenyl-2-oxidanylidene-3,13-diazatricyclo[7.3.1.0^{3,7}]tridecane-4-carboxylic acid (3 entities in total)
• 機能のキーワード: fkbp51, inhibitor, complex, isomerase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 14477.40

構造登録者

Meyners, C.,Krajczy, P.,Hausch, F. (登録日: 2024-04-09, 公開日: 2024-06-12, 最終更新日: 2024-08-28)

主引用文献

Krajczy, P.,Meyners, C.,Repity, M.L.,Hausch, F.
Structure-Based Design of Ultrapotent Tricyclic Ligands for FK506-Binding Proteins.
Chemistry, 30:e202401405-e202401405, 2024

PubMed Abstract: Access to small, rigid, and sp-rich molecules is a major limitation in the drug discovery for challenging protein targets. FK506-binding proteins hold high potential as drug targets or enablers of molecular glues but are fastidious in the chemotypes accepted as ligands. We here report an enantioselective synthesis of a highly rigidified pipecolate-mimicking tricyclic scaffold that precisely positions functional groups for interacting with FKBPs. This was enabled by a 14-step gram-scale synthesis featuring anodic oxidation, stereospecific vinylation, and N-acyl iminium cyclization. Structure-based optimization resulted in the discovery of FKBP inhibitors with picomolar biochemical and subnanomolar cellular activity that represent the most potent FKBP ligands known to date.

PubMed: 38837733
DOI: 10.1002/chem.202401405

実験手法

X-RAY DIFFRACTION (1.16 Å)