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6OFY

Crystal Structure of Arachidonic Acid bound to V349I murine COX-2

Summary for 6OFY
Entry DOI10.2210/pdb6ofy/pdb
DescriptorProstaglandin G/H synthase 2, 2-acetamido-2-deoxy-beta-D-glucopyranose, PROTOPORPHYRIN IX CONTAINING CO, ... (7 entities in total)
Functional Keywordsarachidonic acid cyclooxygenase prostaglandin endoperoxide synthase, membrane protein, oxidoreductase
Biological sourceMus musculus (Mouse)
Total number of polymer chains2
Total formula weight131207.35
Authors
Malkowski, M.G. (deposition date: 2019-04-01, release date: 2020-02-05, Last modification date: 2024-11-20)
Primary citationDong, L.,Anderson, A.J.,Malkowski, M.G.
Arg-513 and Leu-531 Are Key Residues Governing Time-Dependent Inhibition of Cyclooxygenase-2 by Aspirin and Celebrex.
Biochemistry, 58:3990-4002, 2019
Cited by
PubMed Abstract: Aspirin and Celebrex are well-known time-dependent inhibitors of the cyclooxygenases (COX). Molecular dynamics simulations suggest that Arg-513 and Leu-531 contribute to the structural mechanisms of COX inhibition. We used mutagenesis and functional analyses to characterize how substitutions at these positions influence time-dependent inhibition by aspirin and Celebrex. We show that substitutions of Leu-531 with asparagine and phenylalanine significantly attenuate time-dependent inhibition of COX-2 by these drugs. The introduction of side chain bulk, rigidity, and charge would disrupt the formation of the initial noncovalent complex, in the case of aspirin, and the "high-affinity" binding state, in the case of Celebrex. Substitution of Arg-513 with histidine (the equivalent residue in COX-1) resulted in a 2-fold potentiation of aspirin inhibition, in support of the hypothesis that the presence of histidine in COX-1 lowers the activation barrier associated with the formation of the initial noncovalent enzyme-inhibitor complex. As a corollary, we previously hypothesized that the flexibility associated with Leu-531 contributes to the binding of arachidonic acid (AA) to acetylated COX-2 to generate 15-hydroxyeicosatetraenoic acid (15R-HETE). We determined the X-ray crystal structure of AA bound to Co-protoporphyrin IX-reconstituted V349I murine COX-2 (muCOX-2). V349I muCOX-2 was utilized as a surrogate to trap AA in a conformation leading to 15R-HETE. AA binds in a C-shaped pose, facilitated by the rotation of the Leu-531 side chain. Ile-349 is positioned to sterically shield antarafacial oxygen addition at carbon-15 in a manner similar to that proposed for the acetylated Ser-530 side chain.
PubMed: 31469551
DOI: 10.1021/acs.biochem.9b00659
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.2 Å)
Structure validation

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