3ZEB

A complex of GlpG with isocoumarin inhibitor covalently bonded to serine 201 and histidine 150

3ZEB の概要

• エントリーDOI: 10.2210/pdb3zeb/pdb
• 分子名称: RHOMBOID PROTEASE GLPG, 2-phenylethyl 2-(4-azanyl-2-methanoyl-phenyl)ethanoate, CHLORIDE ION, ... (5 entities in total)
• 機能のキーワード: hydrolase, intra-membrane protease, serine protease, acyl enzyme
• 由来する生物種: ESCHERICHIA COLI
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 22064.77

構造登録者

Vinothkumar, K.R.,voskya, O.,Kuettler, E.V.,Brouwer, A.J.,Liskamp, R.M.J.,Verhelst, S.H.L. (登録日: 2012-12-04, 公開日: 2013-02-13, 最終更新日: 2024-11-13)

主引用文献

Vosyka, O.,Vinothkumar, K.R.,Wolf, E.V.,Brouwer, A.J.,Liskamp, R.M.J.,Verhelst, S.H.L.
Activity-Based Probes for Rhomboid Proteases Discovered in a Mass Spectrometry-Based Assay.
Proc.Natl.Acad.Sci.USA, 110:2472-, 2013

PubMed Abstract: Rhomboid proteases are evolutionary conserved intramembrane serine proteases. Because of their emerging role in many important biological pathways, rhomboids are potential drug targets. Unfortunately, few chemical tools are available for their study. Here, we describe a mass spectrometry-based assay to measure rhomboid substrate cleavage and inhibition. We have identified isocoumarin inhibitors and developed activity-based probes for rhomboid proteases. The probes can distinguish between active and inactive rhomboids due to covalent, reversible binding of the active-site serine and stable modification of a histidine residue. Finally, the structure of an isocoumarin-based inhibitor with Escherichia coli rhomboid GlpG uncovers an unusual mode of binding at the active site and suggests that the interactions between the 3-substituent on the isocoumarin inhibitor and hydrophobic residues on the protease reflect S' subsite binding. Overall, these probes represent valuable tools for rhomboid study, and the structural insights may facilitate future inhibitor design.

PubMed: 23359682
DOI: 10.1073/PNAS.1215076110

実験手法

X-RAY DIFFRACTION (2.2 Å)