7BA0

Structure of the FKBP51FK1 domain in complex with the macrocyclic SAFit analogue 63

Summary for 7BA0

• Entry DOI: 10.2210/pdb7ba0/pdb
• Descriptor: Peptidyl-prolyl cis-trans isomerase FKBP5, 2-cyclohexyl-12-[2-(3,4-dimethoxyphenyl)ethyl]-20,21-dihydroxy-25,28-dimethoxy-11,18,23-trioxa-4-azatetracyclo[22.2.2.113,17.04,9]nonacosa-1(26),13(29),14,16,24,27-hexaene-3,10-dione (3 entities in total)
• Functional Keywords: inhibitor, complex, safit, fkbp, isomerase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 15035.27

Authors

Bauder, M.,Meyners, C.,Purder, P.,Merz, S.,Voll, A.,Heymann, T.,Hausch, F. (deposition date: 2020-12-15, release date: 2021-03-17, Last modification date: 2024-01-31)

Primary citation

Bauder, M.,Meyners, C.,Purder, P.L.,Merz, S.,Sugiarto, W.O.,Voll, A.M.,Heymann, T.,Hausch, F.
Structure-Based Design of High-Affinity Macrocyclic FKBP51 Inhibitors.
J.Med.Chem., 64:3320-3349, 2021

PubMed Abstract: The FK506-binding protein 51 (FKBP51) emerged as a key player in several diseases like stress-related disorders, chronic pain, and obesity. Linear analogues of FK506 called SAFit were shown to be highly selective for FKBP51 over its closest homologue FKBP52, allowing the proof-of-concept studies in animal models. Here, we designed and synthesized the first macrocyclic FKBP51-selective ligands to stabilize the active conformation. All macrocycles retained full FKBP51 affinity and selectivity over FKBP52 and the incorporation of polar functionalities further enhanced affinity. Six high-resolution crystal structures of macrocyclic inhibitors in complex with FKBP51 confirmed the desired selectivity-enabling binding mode. Our results show that macrocyclization is a viable strategy to target the shallow FKBP51 binding site selectively.

PubMed: 33666419
DOI: 10.1021/acs.jmedchem.0c02195

Experimental method

X-RAY DIFFRACTION (1.14 Å)