Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	Cryo-EM structures of human arachidonate 12S-lipoxygenase bound to endogenous and exogenous inhibitors.
Journal, issue, pages	Blood, Vol. 142, Issue 14, Page 1233-1242, Year 2023
Publish date	Jul 28, 2023
Authors	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 Abstract	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.
External links	Blood / PubMed:37506345 / PubMed Central
Methods	EM (single particle)
Resolution	2.05 - 2.76 Å
Structure data	40039 8ghb EMDB-40039, PDB-8ghb: The structure of h12-LOX in monomeric form Method: EM (single particle) / Resolution: 2.76 Å 40040 8ghc EMDB-40040, PDB-8ghc: The structure of h12-LOX in dimeric form Method: EM (single particle) / Resolution: 2.3 Å 40041 8ghd EMDB-40041, PDB-8ghd: The structure of h12-LOX in hexameric form bound to inhibitor ML355 and arachidonic acid Method: EM (single particle) / Resolution: 2.2 Å 40042 8ghe EMDB-40042, PDB-8ghe: The structure of h12-LOX in tetrameric form bound to endogenous inhibitor oleoyl-CoA Method: EM (single particle) / Resolution: 2.05 Å EMDB-40299: Consensus refinement of the h12-LOX in a dimeric form Method: EM (single particle) / Resolution: 2.53 Å EMDB-40300: The local refinement map of a "closed" subunit of a 12-LOX dimer Method: EM (single particle) / Resolution: 2.54 Å EMDB-40301: The local refinement map of an "open" subunit of a 12-LOX dimer Method: EM (single particle) / Resolution: 2.33 Å EMDB-40302: The consensus map of a 12-LOX hexamer Method: EM (single particle) / Resolution: 2.63 Å EMDB-40304: The local refinement map of a single subunit of a 12-LOX hexamer Method: EM (single particle) / Resolution: 2.24 Å
Chemicals	ChemComp-FE2: Unknown entry ChemComp-ZR5: N-(1,3-benzothiazol-2-yl)-4-{[(2-hydroxy-3-methoxyphenyl)methyl]amino}benzene-1-sulfonamide ChemComp-ACD: ARACHIDONIC ACID 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) ChemComp-HOH: WATER
Source	homo sapiens (human)
Keywords	OXIDOREDUCTASE / Lipoxygenase / platelets / lipid-modifying enzyme / lipid oxidation / OXIDOREDUCTASE/INHIBITOR / OXIDOREDUCTASE-INHIBITOR complex