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The productive conformation of prostaglandin G at the peroxidase site of prostaglandin endoperoxide H synthase: Docking, molecular dynamics, and site-directed mutagenesis studies

Biochemistry, ISSN: 0006-2960, Vol: 45, Issue: 3, Page: 811-820
2006
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Article Description

We present a plausible productive conformation obtained by docking calculations for the binding of prostaglandin G (PGG) to the peroxidase site of prostaglandin endoperoxide H synthase-1 (PGHS-1, COX-1). The enzyme-substrate complex stability was verified by molecular dynamics. Structural analysis reveals the requirements for enzyme-substrate recognition and binding: the PGG 15-hydroperoxide group is in the proximity of the heme iron and participates in a hydrogen bond network with the conserved His207 and Gln203 and a water molecule, whereas the carboxylate group forms salt bridges with the remote Lys215 and Lys222. Site-directed mutagenesis showed that a single mutation of Lys215 or Lys222 does not affect enzyme activity, whereas dual mutation of these residues, to either alanine or glutamate, significantly decreases turnover. This indicates that the conserved cationic pocket is involved in enzyme-substrate binding. © 2006 American Chemical Society.

Bibliographic Details

Chubb, Anthony J; Fitzgerald, Desmond J; Nolan, Kevin B; Moman, Edelmiro

American Chemical Society (ACS)

Biochemistry, Genetics and Molecular Biology

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