9GON

Crystal structure of DPP9 in complex with sulphostin

これはPDB形式変換不可エントリーです。

9GON の概要

• エントリーDOI: 10.2210/pdb9gon/pdb
• 分子名称: Dipeptidyl peptidase 9, azanyl-oxidanylidene-(sulfoamino)phosphanium, DI(HYDROXYETHYL)ETHER, ... (8 entities in total)
• 機能のキーワード: dipeptidyl peptidase, dipeptidyl peptidase inhibitor, transferase
• 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: 396252.26

構造登録者

Sewald, L.,Tabak, W.W.A.,Fehr, L.,Zolg, S.,Najdzion, M.,Verhoef, C.J.A.,Podlesainski, D.,Geiss-Friedlander, R.,Lammens, A.,Kaschani, F.,Hellerschmied, D.,Huber, R.,Kaiser, M. (登録日: 2024-09-05, 公開日: 2025-07-16)

主引用文献

Sewald, L.,Tabak, W.W.A.,Fehr, L.,Zolg, S.,Najdzion, M.,Verhoef, C.J.A.,Podlesainski, D.,Geiss-Friedlander, R.,Lammens, A.,Kaschani, F.,Hellerschmied, D.,Huber, R.,Kaiser, M.
Sulphostin-inspired N-phosphonopiperidones as selective covalent DPP8 and DPP9 inhibitors.
Nat Commun, 16:3208-3208, 2025

PubMed Abstract: Covalent chemical probes and drugs combine unique pharmacologic properties with the availability of straightforward compound profiling technologies via chemoproteomic platforms. These advantages have fostered the development of suitable electrophilic "warheads" for systematic covalent chemical probe discovery. Despite undisputable advances in the last years, the targeted development of proteome-wide selective covalent probes remains a challenge for dipeptidyl peptidase (DPP) 8 and 9 (DPP8/9), intracellular serine hydrolases of the pharmacologically relevant dipeptidyl peptidase 4 activity/structure homologues (DASH) family. Here, we show the exploration of the natural product Sulphostin, a DPP4 inhibitor, as a starting point for DPP8/9 inhibitor development. The generation of Sulphostin-inspired N-phosphonopiperidones leads to derivatives with improved DPP8/9 inhibitory potency, an enhanced proteome-wide selectivity and confirmed DPP8/9 engagement in cells, thereby representing that structural fine-tuning of the warhead's leaving group may represent a straightforward strategy for achieving target selectivity in exoproteases such as DPPs.

PubMed: 40180908
DOI: 10.1038/s41467-025-58493-z

実験手法

X-RAY DIFFRACTION (1.89 Å)