7AOU

The Fk1 domain of FKBP51 in complex with (2'R,5'S,12'R)-12'-cyclohexyl-2'-[2-(3,4-dimethoxyphenyl)ethyl]-3',19'-dioxa-10',13',16'-triazaspiro[cyclopropane-1,15'- tricyclo[18.3.1.0-5,10]tetracosane]-1'(24'),20',22'-triene-4',11',14',17'-tetrone

Summary for 7AOU

• Entry DOI: 10.2210/pdb7aou/pdb
• Descriptor: Peptidyl-prolyl cis-trans isomerase FKBP5, (2'R,5'S,12'R)-12'-cyclohexyl-2'-[2-(3,4-dimethoxyphenyl)ethyl]-3',19'-dioxa-10',13',16'-triazaspiro[cyclopropane-1,15'- tricyclo[18.3.1.0-5,10]tetracosane]-1'(24'),20',22'-triene-4',11',14',17'-tetrone (3 entities in total)
• Functional Keywords: fkbp51, chaperone, immunophilin, macrocycle, transient binding pocket, isomerase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 14687.86

Authors

Voll, M.A.,Meyners, C.,Heymann, T.,Merz, S.,Purder, P.,Bracher, A.,Hausch, F. (deposition date: 2020-10-15, release date: 2021-04-21, Last modification date: 2024-01-31)

Primary citation

Voll, A.M.,Meyners, C.,Taubert, M.C.,Bajaj, T.,Heymann, T.,Merz, S.,Charalampidou, A.,Kolos, J.,Purder, P.L.,Geiger, T.M.,Wessig, P.,Gassen, N.C.,Bracher, A.,Hausch, F.
Macrocyclic FKBP51 Ligands Define a Transient Binding Mode with Enhanced Selectivity.
Angew.Chem.Int.Ed.Engl., 60:13257-13263, 2021

PubMed Abstract: Subtype selectivity represents a challenge in many drug discovery campaigns. A typical example is the FK506 binding protein 51 (FKBP51), which has emerged as an attractive drug target. The most advanced FKBP51 ligands of the SAFit class are highly selective vs. FKBP52 but poorly discriminate against the homologs and off-targets FKBP12 and FKBP12.6. During a macrocyclization pilot study, we observed that many of these macrocyclic analogs have unanticipated and unprecedented preference for FKBP51 over FKBP12 and FKBP12.6. Structural studies revealed that these macrocycles bind with a new binding mode featuring a transient conformation, which is disfavored for the small FKBPs. Using a conformation-sensitive assay we show that this binding mode occurs in solution and is characteristic for this new class of compounds. The discovered macrocycles are non-immunosuppressive, engage FKBP51 in cells, and block the cellular effect of FKBP51 on IKKα. Our findings provide a new chemical scaffold for improved FKBP51 ligands and the structural basis for enhanced selectivity.

PubMed: 33843131
DOI: 10.1002/anie.202017352

Experimental method

X-RAY DIFFRACTION (1.16 Å)