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Inhibitor complexes of the Pseudomonas serine-carboxyl proteinase

  1. Author:
    Wlodawer, A.
    Li, M.
    Gustchina, A.
    Dauter, Z.
    Uchida, K.
    Oyama, H.
    Goldfarb, N. E.
    Dunn, B. M.
    Oda, K.

  2. Author Address

    NCI, Prot Struct Sect, Macromol Crystallog Lab, Frederick, MD 21702 USA. NCI, Prot Struct Sect, Macromol Crystallog Lab, Frederick, MD 21702 USA. NCI, Intramural Res Support Program, SAIC Frederick, Frederick, MD 21702 USA. NCI, Synchrotron Radiat Res Sect, Macromol Crystallog Lab, Upton, NY 11973 USA. Brookhaven Natl Lab, NSLS, Upton, NY 11973 USA. Teikyo Univ, Sch Sci & Engn, Dept Biosci, Utsunomiya, Tochigi 3208551, Japan. Kyoto Inst Technol, Fac Text Sci, Dept Appl Biol, Sakyo Ku, Kyoto 6068585, Japan. Univ Florida, Dept Biochem & Mol Biol, Gainesville, FL 32610 USA. Wlodawer A NCI, Prot Struct Sect, Macromol Crystallog Lab, Frederick, MD 21702 USA.
    1. Year: 2001
  2. Journal: Biochemistry
    1. 40
    2. 51
    3. Pages: 15602-15611
  4. Type of Article: Article
  1. Abstract:

    Crystal structures of the serine-carboxyl proteinase from Pseudomonas sp. 101 (PSCP), complexed with a number of inhibitors, have been solved and refined at high- to atomic- level resolution. All of these inhibitors (tyrostatin, pseudo- tyrostatin, AcIPF, AcIAF, and chymostatin, as well as previously studied iodotyrostatin and pseudo-iodotyrostatin) make covalent bonds to the active site Ser287 through their aldehyde moieties, while their side chains occupy subsites S1- S4 of the enzyme. The mode of binding of the inhibitors is almost identical for their P1 and P2 side chains, while significant differences are observed for P3 and P4 (if present). Kinetic parameters for the binding of these nanomolar inhibitors to PSCP have been established and correlated with the observed mode of binding. The preferences of this enzyme for a larger side chain in P2 as well as Tyr or Phe in P1 are explained by the size, shape, and characteristics of the S2 and S1 regions of the protein structure, respectively. Networks of hydrogen bonds involving glutamic and aspartic acids have been analyzed for the atomic-resolution structure of the native enzyme. PSCP contains a calcium-binding site that consists of Asp328, Asp348, three amide carbonyl groups, and a water molecule, in almost perfect octahedral coordination. The presence of Ca2+ cation is necessary for the activity of the enzyme.

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