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

摘要: Summary PTGR2 catalyzes an NADPH-dependent reduction of the conjugated α,β-unsaturated double bond of 15-keto-PGE 2 , a key step in terminal inactivation prostaglandins and suppression PPARγ-mediated adipocyte differentiation. Selective inhibition may contribute to the improvement insulin sensitivity with fewer side effects. belongs medium-chain dehydrogenase/reductase superfamily. The crystal structures reported here reveal features NADPH binding-induced conformational change LID motif polyproline type II helix which are critical for reaction. Mutation Tyr64 Tyr259 significantly reduces rate catalysis but increases affinity substrate, confirming structural observations. Besides targeting cyclooxygenase, indomethacin also inhibits binding mode similar that . becomes highly disordered upon indomethacin, indicating plasticity active site. This study has implications rational design inhibitors PTGR2.