6DXX

Human N-acylethanolamine-hydrolyzing acid amidase (NAAA) in complex with non-covalent benzothiazole-piperazine inhibitor ARN19702, in presence of Triton X-100

6DXX の概要

• エントリーDOI: 10.2210/pdb6dxx/pdb
• 分子名称: N-acylethanolamine-hydrolyzing acid amidase subunit alpha, N-acylethanolamine-hydrolyzing acid amidase subunit beta, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (9 entities in total)
• 機能のキーワード: endocannabinoid, lipase, hydrolase
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 120492.68

構造登録者

Gorelik, A.,Gebai, A.,Illes, K.,Piomelli, D.,Nagar, B. (登録日: 2018-07-01, 公開日: 2018-09-26, 最終更新日: 2024-11-13)

主引用文献

Gorelik, A.,Gebai, A.,Illes, K.,Piomelli, D.,Nagar, B.
Molecular mechanism of activation of the immunoregulatory amidase NAAA.
Proc. Natl. Acad. Sci. U.S.A., 115:E10032-E10040, 2018

PubMed Abstract: Palmitoylethanolamide is a bioactive lipid that strongly alleviates pain and inflammation in animal models and in humans. Its signaling activity is terminated through degradation by -acylethanolamine acid amidase (NAAA), a cysteine hydrolase expressed at high levels in immune cells. Pharmacological inhibitors of NAAA activity exert profound analgesic and antiinflammatory effects in rodent models, pointing to this protein as a potential target for therapeutic drug discovery. To facilitate these efforts and to better understand the molecular mechanism of action of NAAA, we determined crystal structures of this enzyme in various activation states and in complex with several ligands, including both a covalent and a reversible inhibitor. Self-proteolysis exposes the otherwise buried active site of NAAA to allow catalysis. Formation of a stable substrate- or inhibitor-binding site appears to be conformationally coupled to the interaction of a pair of hydrophobic helices in the enzyme with lipid membranes, resulting in the creation of a linear hydrophobic cavity near the active site that accommodates the ligand's acyl chain.

PubMed: 30301806
DOI: 10.1073/pnas.1811759115

実験手法

X-RAY DIFFRACTION (2.7 Å)