Structural Basis for Catalytic and Inhibitory Mechanisms of Human Prostaglandin Reductase PTGR2

Yu Hauh Wu, Tzu Ping Ko, Rey Ting Guo, Su Ming Hu, Lee Ming Chuang, Andrew H H.J. Wang

Research output: Contribution to journalArticlepeer-review

38 Citations (Scopus)


PTGR2 catalyzes an NADPH-dependent reduction of the conjugated α,β-unsaturated double bond of 15-keto-PGE2, a key step in terminal inactivation of prostaglandins and suppression of PPARγ-mediated adipocyte differentiation. Selective inhibition of PTGR2 may contribute to the improvement of insulin sensitivity with fewer side effects. PTGR2 belongs to the medium-chain dehydrogenase/reductase superfamily. The crystal structures reported here reveal features of the NADPH binding-induced conformational change in a LID motif and a polyproline type II helix which are critical for the reaction. Mutation of Tyr64 and Tyr259 significantly reduces the rate of catalysis but increases the affinity to substrate, confirming the structural observations. Besides targeting cyclooxygenase, indomethacin also inhibits PTGR2 with a binding mode similar to that of 15-keto-PGE2. The LID motif becomes highly disordered upon the binding of indomethacin, indicating plasticity of the active site. This study has implications for the rational design of inhibitors of PTGR2.

Original languageEnglish
Pages (from-to)1714-1723
Number of pages10
Issue number11
Publication statusPublished - Nov 12 2008
Externally publishedYes



ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology


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