7B9Z

Structure of the FKBP51FK1 domain in complex with the macrocyclic SAFit analogue 35-(E)

7B9Z の概要

• エントリーDOI: 10.2210/pdb7b9z/pdb
• 分子名称: Peptidyl-prolyl cis-trans isomerase FKBP5, 2-cyclohexyl-12-[2-(3,4-dimethoxyphenyl)ethyl]-25,26-dimethoxy-11,18,23-trioxa-4-azatetracyclo[22.3.1.113,17.04,9]nonacosa-1(27),13(29),14,16,20,24(28),25-heptaene-3,10-dione, isothiocyanate, ... (4 entities in total)
• 機能のキーワード: inhibitor, complex, safit, fkbp, 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: 15178.52

構造登録者

Bauder, M.,Meyners, C.,Purder, P.,Merz, S.,Voll, A.,Heymann, T.,Hausch, F. (登録日: 2020-12-15, 公開日: 2021-03-17, 最終更新日: 2024-01-31)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.44 Å)