7APQ

The Fk1 domain of FKBP51 in complex with (1S,5S,6R)-10-(benzo[d]thiazol-6-ylsulfonyl)-5-(methoxymethyl)-3-(pyridin-2-ylmethyl)-3,10-diazabicyclo[4.3.1]decan-2-one

7APQ の概要

• エントリーDOI: 10.2210/pdb7apq/pdb
• 分子名称: Peptidyl-prolyl cis-trans isomerase FKBP5, (1~{S},5~{S},6~{R})-10-(1,3-benzothiazol-6-ylsulfonyl)-5-(methoxymethyl)-3-(pyridin-2-ylmethyl)-3,10-diazabicyclo[4.3.1]decan-2-one (3 entities in total)
• 機能のキーワード: conformation analysis, density functional calculations, fkbps, magic methyl, 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: 14512.68

構造登録者

Kolos, M.J.,Pomplun, S.,Riess, B.,Purder, P.,Voll, M.A.,Merz, S.,Bracher, A.,Meyners, C.,Krewald, V.,Hausch, F. (登録日: 2020-10-19, 公開日: 2021-11-10, 最終更新日: 2024-01-31)

主引用文献

Kolos, J.M.,Pomplun, S.,Jung, S.,Riess, B.,Purder, P.L.,Voll, A.M.,Merz, S.,Gnatzy, M.,Geiger, T.M.,Quist-Lokken, I.,Jatzlau, J.,Knaus, P.,Holien, T.,Bracher, A.,Meyners, C.,Czodrowski, P.,Krewald, V.,Hausch, F.
Picomolar FKBP inhibitors enabled by a single water-displacing methyl group in bicyclic [4.3.1] aza-amides.
Chem Sci, 12:14758-14765, 2021

PubMed Abstract: Methyl groups can have profound effects in drug discovery but the underlying mechanisms are diverse and incompletely understood. Here we report the stereospecific effect of a single, solvent-exposed methyl group in bicyclic [4.3.1] aza-amides, robustly leading to a 2 to 10-fold increase in binding affinity for FK506-binding proteins (FKBPs). This resulted in the most potent and efficient FKBP ligands known to date. By a combination of co-crystal structures, isothermal titration calorimetry (ITC), density-functional theory (DFT), and 3D reference interaction site model (3D-RISM) calculations we elucidated the origin of the observed affinity boost, which was purely entropically driven and relied on the displacement of a water molecule at the protein-ligand-bulk solvent interface. The best compounds potently occupied FKBPs in cells and enhanced bone morphogenic protein (BMP) signaling. Our results show how subtle manipulation of the solvent network can be used to design atom-efficient ligands for difficult, solvent-exposed binding pockets.

PubMed: 34820091
DOI: 10.1039/d1sc04638a

実験手法

X-RAY DIFFRACTION (1.09 Å)