8JUB

Crystal structure of glutaminase C in complex with compound 27

8JUB の概要

• エントリーDOI: 10.2210/pdb8jub/pdb
• 分子名称: Glutaminase kidney isoform, mitochondrial, 3-[2-oxidanylidene-2-[[5-[[(3R)-1-pyridazin-3-ylpyrrolidin-3-yl]amino]-1,3,4-thiadiazol-2-yl]amino]ethyl]benzoic acid (3 entities in total)
• 機能のキーワード: inhibitor, complex, antitumor protein, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 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: 235974.36

構造登録者

Wang, X.,Hanyu, S.,Tingting, D. (登録日: 2023-06-26, 公開日: 2023-10-11, 最終更新日: 2023-11-01)

主引用文献

Sun, H.,Du, T.,Yang, M.,Liu, X.,Xue, X.,Chen, K.,Lang, X.,Chen, X.,Wang, B.,Wang, X.
Targeting the Subpocket Enables the Discovery of Thiadiazole-Pyridazine Derivatives as Glutaminase C Inhibitors.
Acs Med.Chem.Lett., 14:1455-1466, 2023

PubMed Abstract: As glutaminase C (GAC) has become an attractive target for cancer treatment by regulating glutaminolysis, thus, interest in GAC inhibitors has risen in recent years. Herein, a potential binding subpocket comprising basic residues was identified, and through extensive structure-activity relationship studies, promising inhibitors and were identified with robust GAC inhibitory activity and A549 cell antiproliferative activity. X-ray crystallography of the -GAC and -GAC complexes revealed a novel binding mode against GAC. The potency of and against GAC further highlighted the importance of the binding. Notably, compounds and regulated the cellular metabolite, thereby increasing reactive oxygen species by blocking glutamine metabolism. Compound also exhibited excellent antiproliferative activity in the A549 cell xenograft model. We further proved that is a safe GAC allosteric inhibitor. A basic subpocket is proposed that might provide new strategies for the development of novel GAC inhibitors in the future.

PubMed: 37849538
DOI: 10.1021/acsmedchemlett.3c00375

実験手法

X-RAY DIFFRACTION (2.01 Å)