4O7D

Crystal structure of human glutaminase in complex DON

4O7D の概要

• エントリーDOI: 10.2210/pdb4o7d/pdb
• 分子名称: Glutaminase kidney isoform, mitochondrial, 5-OXO-L-NORLEUCINE (3 entities in total)
• 機能のキーワード: hydrolase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Isoform 1: Cytoplasm, cytosol. Isoform 3: Mitochondrion: O94925
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34606.51

構造登録者

Thangavelu, K.,Sivaraman, J. (登録日: 2013-12-24, 公開日: 2014-04-16, 最終更新日: 2025-03-26)

主引用文献

Thangavelu, K.,Chong, Q.Y.,Low, B.C.,Sivaraman, J.
Structural basis for the active site inhibition mechanism of human kidney-type glutaminase (KGA)
Sci Rep, 4:3827-3827, 2014

PubMed Abstract: Glutaminase is a metabolic enzyme responsible for glutaminolysis, a process harnessed by cancer cells to feed their accelerated growth and proliferation. Among the glutaminase isoforms, human kidney-type glutaminase (KGA) is often upregulated in cancer and is thus touted as an attractive drug target. Here we report the active site inhibition mechanism of KGA through the crystal structure of the catalytic domain of KGA (cKGA) in complex with 6-diazo-5-oxo-L-norleucine (DON), a substrate analogue of glutamine. DON covalently binds with the active site Ser286 and interacts with residues such as Tyr249, Asn335, Glu381, Asn388, Tyr414, Tyr466 and Val484. The nucleophilic attack of Ser286 sidechain on DON releases the diazo group (N2) from the inhibitor and results in the formation of an enzyme-inhibitor complex. Mutational studies confirmed the key role of these residues in the activity of KGA. This study will be important in the development of KGA active site inhibitors for therapeutic interventions.

PubMed: 24451979
DOI: 10.1038/srep03827

実験手法

X-RAY DIFFRACTION (2.3 Å)