ArticleThe Journal of biological chemistry2010
Structural basis of fatty acid substrate binding to cyclooxygenase-2.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 83 papers.
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Who cites it
83 citing papers in PubMed, 162 citations in OpenAlex.
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- Catalytic and structural comparisons of linoleate dioxygenases and their cytochrome P450 companions with enzymes of the cyclooxygenase cascade.The Journal of biological chemistry · 2026Review
- Computational strategies for unraveling insights from known inhibitors for further lead optimization: A case study on Celecoxib analogues.Scientific reports · 2026Article
- Lipopolysaccharide induced mouse depression model can better simulate changes in peripheral blood FFAs in alMDD.PloS one · 2026Article
- Allosteric regulation of prostaglandin endoperoxide HThe Journal of biological chemistry · 2025Review
- Octadecanoids as emerging lipid mediators in cnidarian-dinoflagellate symbiosis.Communications biology · 2025Article
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- 2-Hydroxybenzohydrazide as a novel potential candidate against nociception, inflammation, and pyrexia: in vitro, in vivo, and computational approaches.Inflammopharmacology · 2024Article
- Defining the Conformational Ensembles Associated with Ligand Binding to Cyclooxygenase-2.Biochemistry · 2023Article
- Current Insights into the Use of Probiotics and Fatty Acids in Alleviating Depression.Microorganisms · 2023Review
- Structural insights into the half-of-sites reactivity in homodimeric and homotetrameric metalloenzymes.Current opinion in chemical biology · 2023Review
- Synthesis and In Vitro Biological Evaluation ofMolecules (Basel, Switzerland) · 2023Article
- Carvacrol-A Natural Phenolic Compound with Antimicrobial Properties.Antibiotics (Basel, Switzerland) · 2023Review
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- Pharmacology activity, toxicity, and clinical trials of Erythrina genus plants (Fabaceae): an evidence-based review.Frontiers in pharmacology · 2023Review
23 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
The cyclooxygenases (COX-1 and COX-2) are membrane-associated heme-containing homodimers that generate prostaglandin H(2) from arachidonic acid (AA). Although AA is the preferred substrate, other fatty acids are oxygenated by these enzymes with varying efficiencies. We determined the crystal structures of AA, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) bound to Co(3+)-protoporphyrin IX-reconstituted murine COX-2 to 2.1, 2.4, and 2.65 A, respectively. AA, EPA, and docosahexaenoic acid bind in different conformations in each monomer constituting the homodimer in their respective structures such that one monomer exhibits nonproductive binding and the other productive binding of the substrate in the cyclooxygenase channel. The interactions identified between protein and substrate when bound to COX-1 are conserved in our COX-2 structures, with the only notable difference being the lack of interaction of the carboxylate of AA and EPA with the side chain of Arg-120. Leu-531 exhibits a different side chain conformation when the nonproductive and productive binding modes of AA are compared. Unlike COX-1, mutating this residue to Ala, Phe, Pro, or Thr did not result in a significant loss of activity or substrate binding affinity. Determination of the L531F:AA crystal structure resulted in AA binding in the same global conformation in each monomer. We speculate that the mobility of the Leu-531 side chain increases the volume available at the opening of the cyclooxygenase channel and contributes to the observed ability of COX-2 to oxygenate a broad spectrum of fatty acid and fatty ester substrates.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.