8CHJ

Human FKBP12 in complex with (1S,5S,6R)-10-((R)-(3,5-dichlorophenyl)sulfonimidoyl)-3-(pyridin-2-ylmethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one

8CHJ の概要

• エントリーDOI: 10.2210/pdb8chj/pdb
• 分子名称: Peptidyl-prolyl cis-trans isomerase FKBP1A, (1S,5S,6R)-10-[[3,5-bis(chloranyl)phenyl]sulfonimidoyl]-5-ethenyl-3-(pyridin-2-ylmethyl)-3,10-diazabicyclo[4.3.1]decan-2-one, DIMETHYL SULFOXIDE, ... (5 entities in total)
• 機能のキーワード: fkbp12, inhibitor, isomerase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 49417.90

構造登録者

Meyners, C.,Purder, P.L.,Hausch, F. (登録日: 2023-02-08, 公開日: 2023-09-06, 最終更新日: 2023-10-11)

主引用文献

Purder, P.L.,Meyners, C.,Sugiarto, W.O.,Kolos, J.,Lohr, F.,Gebel, J.,Nehls, T.,Dotsch, V.,Lermyte, F.,Hausch, F.
Deconstructing Protein Binding of Sulfonamides and Sulfonamide Analogues.
Jacs Au, 3:2478-2486, 2023

PubMed Abstract: Sulfonamides are one of the most important pharmacophores in medicinal chemistry, and sulfonamide analogues have gained substantial interest in recent years. However, the protein interactions of sulfonamides and especially of their analogues are underexplored. Using FKBP12 as a model system, we describe the synthesis of optically pure sulfenamide, sulfinamide, and sulfonimidamide analogues of a well characterized sulfonamide ligand. This allowed us to precisely determine the binding contributions of each sulfonamide oxygen atom and the consequences of nitrogen replacements. We also present high-resolution cocrystal structures of sulfonamide analogues buried in the pocket of a protein target. This revealed intimate contacts with the protein including an unprecedented hydrogen bond acceptor of sulfonimidamides. The use of sulfonamide analogues enabled new exit vectors that allowed remodeling of a subpocket in FKBP12. Our results illuminate the protein interaction potential of sulfonamides/sulfonamide analogues and will aid in their rational design.

PubMed: 37772190
DOI: 10.1021/jacsau.3c00241

実験手法

X-RAY DIFFRACTION (1.697 Å)