7A3J

Crystal structure of DPP8 in complex with a 4-oxo-b-lactam based inhibitor, A272

7A3J の概要

• エントリーDOI: 10.2210/pdb7a3j/pdb
• 関連するPDBエントリー: 6EOP
• 分子名称: Dipeptidyl peptidase 8, 2-ethyl-2-methanoyl-~{N}-[3-[[4-(naphthalen-1-ylmethyl)piperazin-1-yl]methyl]phenyl]butanamide, trimethylamine oxide, ... (5 entities in total)
• 機能のキーワード: dpp8, protease, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 312154.57

構造登録者

Ross, B.H.,Huber, R. (登録日: 2020-08-18, 公開日: 2021-06-30, 最終更新日: 2024-01-31)

主引用文献

Carvalho, L.A.R.,Ross, B.,Fehr, L.,Bolgi, O.,Wohrle, S.,Lum, K.M.,Podlesainski, D.,Vieira, A.C.,Kiefersauer, R.,Felix, R.,Rodrigues, T.,Lucas, S.D.,Gross, O.,Geiss-Friedlander, R.,Cravatt, B.F.,Huber, R.,Kaiser, M.,Moreira, R.
Chemoproteomics-Enabled Identification of 4-Oxo-beta-Lactams as Inhibitors of Dipeptidyl Peptidases 8 and 9.
Angew.Chem.Int.Ed.Engl., 2022

PubMed Abstract: Dipeptidyl peptidases 8 and 9 (DPP8/9) have gathered interest as drug targets due to their important roles in biological processes like immunity and tumorigenesis. Elucidation of their distinct individual functions remains an ongoing task and could benefit from the availability of novel, chemically diverse and selective chemical tools. Here, we report the activity-based protein profiling (ABPP)-mediated discovery of 4-oxo-β-lactams as potent, non-substrate-like nanomolar DPP8/9 inhibitors. X-ray crystallographic structures revealed different ligand binding modes for DPP8 and DPP9, including an unprecedented targeting of an extended S2' (eS2') subsite in DPP8. Biological assays confirmed inhibition at both target and cellular levels. Altogether, our integrated chemical proteomics and structure-guided small molecule design approach led to novel DPP8/9 inhibitors with alternative molecular inhibition mechanisms, delivering the highest selectivity index reported to date.

PubMed: 36089535
DOI: 10.1002/anie.202210498

実験手法

X-RAY DIFFRACTION (3 Å)