Crystal structures of human non -pancreatic secreted phospholipase a2 in complex with each of two different inhibitors

B. H. Oh, S. S. Cha, D. Lee, J. Kurdylar, J. Adams, C. Jones, S. S. Abdel-Meguid

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Human non-pancreatic secreted phospholipase A2 is implicated in inflammatory diseases due to its catalytic activity to produce common precursors for the synthesis of several lipid mediators of inflammation. We have determined crystals structures of the enzyme in complex with each of two different acylamide analogues of phospholipids, one with IC50 of 0.2 μM, and the other with IC50 of 0.013 μM. The lower affinity inhibitor contains a phosphate group at the sn-1 position of the glycerol backbone, and a long 18-C-atom chain at the sn-2 position. The higher affinity inhibitor, which is a selective potent competitive inhibitor of the enzyme, is an extensively modified form of phospholipid containing three benzene rings, an amide group, one sulfur atom, and one carboxyl group in place of a phosphate group. The same number of ionic or hydrogen bonds are found between the inhibitor and enzyme in the two structures, indicating that the tight binding of the higher affinity inhibitor is primarily due to improved hydrophobic interactions. In addition, differential gain of free energy change in transferring the inhibitor from the lipid bilayer to the active site of the activated enzyme on the cell membrane is likely to contribute to the improvement of the binding affinity.

Original languageEnglish
Pages (from-to)A986
JournalFASEB Journal
Issue number6
StatePublished - 1996


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