EMDB/PDB/SASBDBから引用されている文献のデータベース

キーワード
構造解析手法	All X線回折 NMR 電子顕微鏡小角散乱中性子線回折線維回折粉末回折赤外分光 EPR FRET 理論モデルハイブリッド
著者・登録者
ジャーナル
IF	>30 >20 >10 >5 all

タイトル	Cryo-EM structures of human arachidonate 12S-lipoxygenase bound to endogenous and exogenous inhibitors.
ジャーナル・号・ページ	Blood, Vol. 142, Issue 14, Page 1233-1242, Year 2023
掲載日	2023年7月28日
著者	Jesse I Mobbs / Katrina A Black / Michelle Tran / Wessel A C Burger / Hariprasad Venugopal / Theodore R Holman / Michael Holinstat / David M Thal / Alisa Glukhova /
PubMed 要旨	Human 12-lipoxygenase (12-LOX) is a key enzyme involved in platelet activation, and the regulation of its activity has been targeted for the treatment of heparin-induced thrombocytopenia. Despite the ...Human 12-lipoxygenase (12-LOX) is a key enzyme involved in platelet activation, and the regulation of its activity has been targeted for the treatment of heparin-induced thrombocytopenia. Despite the clinical importance of 12-LOX, the exact mechanisms by which it affects platelet activation are not fully understood, and the lack of structural information has limited drug discovery efforts. In this study, we used single-particle cryo-electron microscopy to determine high-resolution structures (1.7-2.8 Å) of human 12-LOX. Our results showed that 12-LOX can exist in multiple oligomeric states, from monomer to hexamer, which may affect its catalytic activity and membrane association. We also identified different conformations within the 12-LOX dimer, which likely represent different time points in its catalytic cycle. Furthermore, we identified small molecules bound to 12-LOX. The active site of the 12-LOX tetramer was occupied by an endogenous 12-LOX inhibitor, a long-chain acyl coenzyme A. In addition, we found that the 12-LOX hexamer can simultaneously bind to arachidonic acid and ML355, a selective 12-LOX inhibitor that has passed a phase 1 clinical trial for the treatment of heparin-induced thrombocytopenia and received a fast-track designation by the Food and Drug Administration. Overall, our findings provide novel insights into the assembly of 12-LOX oligomers, their catalytic mechanism, and small molecule binding, paving the way for further drug development targeting the 12-LOX enzyme.
リンク	Blood / PubMed:37506345 / PubMed Central
手法	EM (単粒子)
解像度	2.05 - 2.76 Å
構造データ	40039 8ghb EMDB-40039, PDB-8ghb: The structure of h12-LOX in monomeric form 手法: EM (単粒子) / 解像度: 2.76 Å 40040 8ghc EMDB-40040, PDB-8ghc: The structure of h12-LOX in dimeric form 手法: EM (単粒子) / 解像度: 2.3 Å 40041 8ghd EMDB-40041, PDB-8ghd: The structure of h12-LOX in hexameric form bound to inhibitor ML355 and arachidonic acid 手法: EM (単粒子) / 解像度: 2.2 Å 40042 8ghe EMDB-40042, PDB-8ghe: The structure of h12-LOX in tetrameric form bound to endogenous inhibitor oleoyl-CoA 手法: EM (単粒子) / 解像度: 2.05 Å EMDB-40299: Consensus refinement of the h12-LOX in a dimeric form 手法: EM (単粒子) / 解像度: 2.53 Å EMDB-40300: The local refinement map of a "closed" subunit of a 12-LOX dimer 手法: EM (単粒子) / 解像度: 2.54 Å EMDB-40301: The local refinement map of an "open" subunit of a 12-LOX dimer 手法: EM (単粒子) / 解像度: 2.33 Å EMDB-40302: The consensus map of a 12-LOX hexamer 手法: EM (単粒子) / 解像度: 2.63 Å EMDB-40304: The local refinement map of a single subunit of a 12-LOX hexamer 手法: EM (単粒子) / 解像度: 2.24 Å
化合物	ChemComp-FE2: Unknown entry ChemComp-ZR5: N-(1,3-benzothiazol-2-yl)-4-{[(2-hydroxy-3-methoxyphenyl)methyl]amino}benzene-1-sulfonamide / N-(2-ベンゾチアゾリル)-4-(2-ヒドロキシ-3-メトキシベンジルアミノ)ベンゼンスルホンアミド ChemComp-ACD: ARACHIDONIC ACID / アラキドン酸 ChemComp-3VV: S-{(3R,5R,9R)-1-[(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-4-hydroxy-3-(phosphonooxy)tetrahydrofuran-2-yl]-3,5,9-trihydroxy-8,8-dimethyl-3,5-dioxido-10,14-dioxo-2,4,6-trioxa-11,15-diaza-3lambda~5~,5lambda~5~-diphosphaheptadecan-17-yl} (9Z)-octadec-9-enethioate (non-preferred name) / オレオイルCoA ChemComp-HOH: WATER
由来	homo sapiens (ヒト)
キーワード	OXIDOREDUCTASE / Lipoxygenase / platelets / lipid-modifying enzyme / lipid oxidation / OXIDOREDUCTASE/INHIBITOR / OXIDOREDUCTASE-INHIBITOR complex