Aspirin effects on COX aka PGHS
THE STRUCTURAL BASIS OF ASPIRIN ACTIVITY INFERRED FROM THE CRYSTAL STRUCTURE OF INACTIVATED PROSTAGLANDIN H2 SYNTHASE
Aspirin exerts its anti-inflammatory effects through selective acetylation of serine 530 on prostaglandin H2 synthase (PGHS), also referred to as cyclooxygenase (COX).
PGHS contains two identical polypeptide chains, shown in blue and green in the box at the right. The enzyme catalyzes two reactions: first, the heme group reacts with the oxygen to create a peroxide; in the second reaction, the peroxide is added to the double bond in arachadonic acid.
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.
About this Structure
1PTH is a 2 chains structure of sequences from Ovis aries. The May 2001 RCSB PDB Molecule of the Month feature on Cyclooxygenase by David S. Goodsell is 10.2210/rcsb_pdb/mom_2001_5. Full crystallographic information is available from OCA.
Reference
- Loll PJ, Picot D, Garavito RM. The structural basis of aspirin activity inferred from the crystal structure of inactivated prostaglandin H2 synthase. Nat Struct Biol. 1995 Aug;2(8):637-43. PMID:7552725
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