• Binding of active site directed ligands to phospholipase A2: Implications on the molecular constraints and catalytic mechanism

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      https://www.ias.ac.in/article/fulltext/jcsc/106/05/1177-1189

    • Keywords

       

      PLA2; inhibitors; catalytic mechanism; molecular modelling; transition state

    • Abstract

       

      Molecular constraints for the localization of active site directed ligands (competitive inhibitors and substrates) in the active site of phospholipase A2 (PLA2) are characterized. Structure activity relationships with known inhibitors suggest that the head group interactions dominate the selectivity as well as a substantial part of the affinity. Theab initio fitting of the amide ligands in the active site was carried out to characterize the head group interactions. Based on a systematic coordinate space search, formamide is docked with known experimental constraints such as coordination of the carbonyl group to Ca2+ and hydrogen bond between amide nitrogen and ND1 of His48. An optimal position for a bound water molecule is identified and its significance for the catalytic mechanism is postulated. Unlike the traditional “pseudo-triad” mechanism, the “Ca-coordinated-oxyanion” mechanism proposed here invokes activation of the catalytic water to form the oxyanion in the coordination sphere of calcium. As it attacks the carbonyl carbon of the ester, a near-tetrahedral intermediate is formed. As the second proton of the catalytic water is abstracted by the ester oxygen, its reorientation and simultaneous cleavage form hydrogen bond with ND1 of His48. In this mechanism of esterolysis, a catalytic role for the water co-ordinated to Ca2+ is recognised.

    • Author Affiliations

       

      K Seshadri1 Saraswathi Vishveshwara1 Mahendra K Jain1 2

      1. Molecular Biophysics Unit, Indian Institute of Science, Bangalore - 560012, India
      2. Department of Chemistry and Biochemistry, University of Delaware, Newark, DE - 19716, USA
    • Dates

       
  • Journal of Chemical Sciences | News

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