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Structural study of the complex between human pepsin and a phosphorus-containing peptidic transition-state analog

  1. Author:
    Fujinaga, M.
    Cherney, M. M.
    Tarasova, N. I.
    Bartlett, P. A.
    Hanson, J. E.
    James, M. N. G.

  2. Author Address

    James MNG Univ Alberta, Dept Biochem, Med Res Council Canada, Grp Prot Struct & Funct Edmonton AB T6G 2H7 Canada Univ Alberta, Dept Biochem, Med Res Council Canada, Grp Prot Struct & Funct Edmonton AB T6G 2H7 Canada NCI, Mol Aspects Drug Design Sect, ABL Basic Res Program, FCDRC Frederick, MD 21702 USA Univ Calif Berkeley, Dept Chem Berkeley, CA 94720 USA
    1. Year: 2000
  2. Journal: Acta Crystallographica Section D-Biological Crystallography
    1. 56
    2. Part 3
    3. Pages: 272-279
  4. Type of Article: Article
  1. Abstract:

    The refined crystal structure of the complex between human pepsin and a synthetic phosphonate inhibitor, Iva-Val-Val-Leu(P)-(O)Phe-Ala-Ala-OMe [Iva = isovaleryl, Leu(P) = the phosphinic acid analog of L-leucine, (O)Phe = L-3-phenyllactic acid, OMe = methyl ester], is presented. The structure was refined using diffraction data between 30 and 1.9 Angstrom resolution to a final R factor (Sigma \ \F-o\ - \F-c\ \/ Sigma \F-o\, where \F-o\ and \F-c\ are the observed and calculated structure-factor amplitudes, respectively) of 20.0%. The interactions of the inhibitor with the enzyme show the locations of the binding sites on the enzyme from S4 to S3'. Modeling of the inhibitor binding to porcine pepsin shows very similar binding sires, except at S4. Comparison of the complex structure with the structures of related inhibitors bound to penicillopepsin helps to rationalize the observed differences in the binding constants. The convergence of reaction mechanisms and geometries in different families of proteinases is also discussed. [References: 37]

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