5DIT

The Fk1 domain of FKBP51 in complex with the new synthetic ligand (1R)-3-(3,4-dimethoxyphenyl)-1-f3-[2-(morpholin-4-yl)ethoxy]phenylgpropyl(2S)-1-[(2S,3R)-2-cyclohexyl-3-hydroxybutanoyl]piperidine-2-carboxylate

Summary for 5DIT

• Entry DOI: 10.2210/pdb5dit/pdb
• Descriptor: Peptidyl-prolyl cis-trans isomerase FKBP5, (1R)-3-(3,4-dimethoxyphenyl)-1-{3-[2-(morpholin-4-yl)ethoxy]phenyl}propyl (2S)-1-[(2S,3R)-2-cyclohexyl-3-hydroxybutanoyl]piperidine-2-carboxylate (3 entities in total)
• Functional Keywords: fk-506 binding domain, hsp90 cochaperone, immunophiline, peptidyl-prolyl isomerase, ligand selectivity, isomerase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: Q13451
• Total number of polymer chains: 1
• Total formula weight: 14706.95

Authors

Feng, X.,Sippel, C.,Bracher, A.,Hausch, F. (deposition date: 2015-09-01, release date: 2015-10-14, Last modification date: 2024-05-08)

Primary citation

Feng, X.,Sippel, C.,Bracher, A.,Hausch, F.
Structure-Affinity Relationship Analysis of Selective FKBP51 Ligands.
J.Med.Chem., 58:7796-7806, 2015

PubMed Abstract: The FK506-binding protein 51 (FKBP51) is a promising drug target for the treatment of stress-related psychiatric or metabolic disorders. Just recently, the first selective ligands for FKBP51 were reported based on an induced fit mechanism, but they are too large for a further drug development process. We therefore designed and synthesized a novel series of selective ligands to explore the requirements necessary for binding to the induced-fit conformation. All ligands of this series show no binding toward the structurally very similar antitarget FKBP52. With the cocrystal structure of the best ligand in this novel series we confirmed the induced fit mechanism. Furthermore, the structure-affinity relationship provides information about beneficial structural features, which is valuable for the development of improved FKBP51-directed drugs.

PubMed: 26419422
DOI: 10.1021/acs.jmedchem.5b00785

Experimental method

X-RAY DIFFRACTION (2.25 Å)