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8J6N

Crystal structure of Cystathionine gamma-lyase in complex with compound 1

8J6N の概要
エントリーDOI10.2210/pdb8j6n/pdb
分子名称Cystathionine gamma-lyase, [6-methyl-4-[(~{E})-(oxamoylhydrazinylidene)methyl]-5-oxidanyl-pyridin-3-yl]methyl dihydrogen phosphate, GLYCEROL, ... (5 entities in total)
機能のキーワードlyase
由来する生物種Rattus norvegicus (Rat)
タンパク質・核酸の鎖数12
化学式量合計520647.25
構造登録者
Hibi, R.,Toma-Fukai, S.,Shimizu, T.,Hanaoka, K. (登録日: 2023-04-26, 公開日: 2024-02-14)
主引用文献Echizen, H.,Hanaoka, K.,Shimamoto, K.,Hibi, R.,Toma-Fukai, S.,Ohno, H.,Sasaki, E.,Komatsu, T.,Ueno, T.,Tsuchiya, Y.,Watanabe, Y.,Otsuka, T.,Saito, H.,Nagatoishi, S.,Tsumoto, K.,Kojima, H.,Okabe, T.,Shimizu, T.,Urano, Y.
Discovery of a cystathionine gamma-lyase (CSE) selective inhibitor targeting active-site pyridoxal 5'-phosphate (PLP) via Schiff base formation.
Sci Rep, 13:16456-16456, 2023
Cited by
PubMed Abstract: D,L-Propargylglycine (PAG) has been widely used as a selective inhibitor to investigate the biological functions of cystathionine γ-lyase (CSE), which catalyzes the formation of reactive sulfur species (RSS). However, PAG also inhibits other PLP (pyridoxal-5'-phosphate)-dependent enzymes such as methionine γ-lyase (MGL) and L-alanine transaminase (ALT), so highly selective CSE inhibitors are still required. Here, we performed high-throughput screening (HTS) of a large chemical library and identified oxamic hydrazide 1 as a potent inhibitor of CSE (IC = 13 ± 1 μM (mean ± S.E.)) with high selectivity over other PLP-dependent enzymes and RSS-generating enzymes. Inhibitor 1 inhibited the enzymatic activity of human CSE in living cells, indicating that it is sufficiently membrane-permeable. X-Ray crystal structure analysis of the complex of rat CSE (rCSE) with 1 revealed that 1 forms a Schiff base linkage with the cofactor PLP in the active site of rCSE. PLP in the active site may be a promising target for development of selective inhibitors of PLP-dependent enzymes, including RSS-generating enzymes such as cystathionine β-synthase (CBS) and cysteinyl-tRNA synthetase 2 (CARS2), which have unique substrate binding pocket structures.
PubMed: 37777556
DOI: 10.1038/s41598-023-43536-6
主引用文献が同じPDBエントリー
実験手法
X-RAY DIFFRACTION (1.9 Å)
構造検証レポート
Validation report summary of 8j6n
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件を2024-11-20に公開中

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