8AB5

Structure of E. coli GlpG in complex with peptide derived inhibitor Ac-VRHA-conh-[4-(4-butyl)-phenoxy-1-phenyl-2-butyl]

8AB5 の概要

• エントリーDOI: 10.2210/pdb8ab5/pdb
• 関連するBIRD辞書のPRD_ID: PRD_002417
• 分子名称: Rhomboid protease GlpG, Ac-VRHA-conh-[4-(4-butyl)-phenoxy-1-phenyl-2-butyl] (3 entities in total)
• 機能のキーワード: rhomboid, protease, glpg, ketoamide, inhibitor, hydrolase
• 由来する生物種: Escherichia coli K-12; 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 42324.36

構造登録者

Skerlova, J.,Polovinkin, V.,Bach, K.,Borshchevskiy, V.,Strisovsky, K. (登録日: 2022-07-04, 公開日: 2023-10-25, 最終更新日: 2024-11-13)

主引用文献

Bach, K.,Dohnalek, J.,Skerlova, J.,Kuzmik, J.,Polachova, E.,Stanchev, S.,Majer, P.,Fanfrlik, J.,Pecina, A.,Rezac, J.,Lepsik, M.,Borshchevskiy, V.,Polovinkin, V.,Strisovsky, K.
Extensive targeting of chemical space at the prime side of ketoamide inhibitors of rhomboid proteases by branched substituents empowers their selectivity and potency.
Eur.J.Med.Chem., 275:116606-116606, 2024

PubMed Abstract: Rhomboid intramembrane serine proteases have been implicated in several pathologies, and emerge as attractive pharmacological target candidates. The most potent and selective rhomboid inhibitors available to date are peptidyl α-ketoamides, but their selectivity for diverse rhomboid proteases and strategies to modulate it in relevant contexts are poorly understood. This gap, together with the lack of suitable in vitro models, hinders ketoamide development for relevant eukaryotic rhomboid enzymes. Here we explore the structure-activity relationship principles of rhomboid inhibiting ketoamides by medicinal chemistry and enzymatic in vitro and in-cell assays with recombinant rhomboid proteases GlpG, human mitochondrial rhomboid PARL and human RHBDL2. We use X-ray crystallography in lipidic cubic phase to understand the binding mode of one of the best ketoamide inhibitors synthesized here containing a branched terminal substituent bound to GlpG. In addition, to extend the interpretation of the co-crystal structure, we use quantum mechanical calculations and quantify the relative importance of interactions along the inhibitor molecule. These combined experimental analyses implicates that more extensive exploration of chemical space at the prime side is unexpectedly powerful for the selectivity of rhomboid inhibiting ketoamides. Together with variations in the peptide sequence at the non-prime side, or its non-peptidic alternatives, this strategy enables targeted tailoring of potent and selective ketoamides towards diverse rhomboid proteases including disease-relevant ones such as PARL and RHBDL2.

PubMed: 38901105
DOI: 10.1016/j.ejmech.2024.116606

実験手法

X-RAY DIFFRACTION (2.4 Å)