PDBsum entry 1diy

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Oxidoreductase PDB id
Protein chain
553 a.a. *
BOG ×4
Waters ×109
* Residue conservation analysis

References listed in PDB file
Key reference
Title The productive conformation of arachidonic acid bound to prostaglandin synthase.
Authors M.G.Malkowski, S.L.Ginell, W.L.Smith, R.M.Garavito.
Ref. Science, 2000, 289, 1933-1937. [DOI no: 10.1126/science.289.5486.1933]
PubMed id 10988074
Prostaglandin H synthase-1 and -2 (PGHS-1 and -2) catalyze the committed step in prostaglandin synthesis and are targets for nonsteroidal anti-inflammatory drugs (NSAIDs) like aspirin. We have determined the structure of PGHS-1 at 3 angstrom resolution with arachidonic acid (AA) bound in a chemically productive conformation. The fatty acid adopts an extended L-shaped conformation that positions the 13proS hydrogen of AA for abstraction by tyrosine-385, the likely radical donor. A space also exists for oxygen addition on the antarafacial surface of the carbon in the 11-position (C-11). While this conformation allows endoperoxide formation between C-11 and C-9, it also implies that a subsequent conformational rearrangement must occur to allow formation of the C-8/C-12 bond and to position C-15 for attack by a second molecule of oxygen.
Figure 3.
Fig. 3. A schematic of interactions between AA and COX channel residues (30). Carbon atoms of AA are yellow, oxygen atoms red, and the 13proS hydrogen blue. All dashed lines represent interactions within 4.0 Å between the specific side chain atom of the protein and AA; the structures AA-1 and AA-2 revealed the same set of 49 contacts. Only two of these contacts between AA and the COX channel residues are hydrophilic. The carboxylate forms a salt bridge to the guanidinium atom of Arg120 (distance = 2.4 Å; angle = 143°) and a hydrogen bond to the OH group of Tyr355 (distance = 3.1 Å; angle = 115°). (Inset) A schematic of the chemical structure of AA.
Figure 4.
Fig. 4. Mechanistic sequence for converting AA to PGG[2] (30). Abstraction of the 13-proS hydrogen by the tyrosyl radical leads to the migration of the radical to C-11 on AA. Attack of molecular oxygen, coming from the base of the COX channel, occurs on the side antarafacial to hydrogen abstraction. As the 11R-peroxyl radical swings over C-8 for an R-side attack on C-9 to form the endoperoxide bridge, C-12 is brought closer to C-8 via rotation about the C-10/C-11 bond allowing the formation of the cyclopentane ring. The movement of C-12 also positions C-15 optimally for addition of a second molecule of oxygen, formation of PGG[2], and the migration of the radical back to Tyr385.
The above figures are reprinted by permission from the AAAs: Science (2000, 289, 1933-1937) copyright 2000.
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