title: The structural basis of aspirin activity inferred from the crystal structure of inactivated prostaglandin H2 synthase.
abstract: Aspirin exerts its anti-inflammatory effects through selective acetylation of serine 530 on prostaglandin H2 synthase (PGHS). Here we present the 3.4 A resolution X-ray crystal structure of PGHS isoform-1 inactivated by the potent aspirin analogue 2-bromoacetoxy-benzoic acid. Acetylation by this analogue abolishes cyclooxygenase activity by steric blockage of the active-site channel and not through a large conformational change. We observe two rotameric states of the acetyl-serine side chain which block the channel to different extents, a result which may explain the dissimilar effects of aspirin on the two PGHS isoforms. We also observe the product salicylic acid binding at a site consistent with its antagonistic effect on aspirin activity.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Chicago, Illinois 60637, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: Loll
authors.forename: D
authors.initials: D
authors.lastname: Picot
authors.forename: R M
authors.initials: RM
authors.lastname: Garavito
mesh_terms: D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D001241:Aspirin / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D012694:Serine; D012756:Sheep
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D012694:Serine; C095840:bromoaspirin; D011451:Prostaglandin-Endoperoxide Synthases; D001241:Aspirin