1O6F
PROLYL OLIGOPEPTIDASE FROM PORCINE BRAIN, D641A MUTANT WITH BOUND PEPTIDE LIGAND SUC-GLY-PRO
Summary for 1O6F
| Entry DOI | 10.2210/pdb1o6f/pdb |
| Related | 1E5T 1E8M 1E8N 1H2W 1H2X 1H2Y 1H2Z 1O6G 1QFM 1QFS |
| Descriptor | Prolyl endopeptidase, GLYCINE, PROLINE, ... (6 entities in total) |
| Functional Keywords | hydrolase, prolyl oligopeptidase, amnesia, alpha/ beta-hydrolase, beta-propeller |
| Biological source | Sus scrofa (Pig) |
| Total number of polymer chains | 1 |
| Total formula weight | 81404.90 |
| Authors | |
| Primary citation | Szeltner, Z.,Rea, D.,Juhasz, T.,Renner, V.,Mucsi, Z.,Orosz, G.,Fulop, V.,Polgar, L. Substrate-dependent competency of the catalytic triad of prolyl oligopeptidase. J. Biol. Chem., 277:44597-44605, 2002 Cited by PubMed Abstract: Prolyl oligopeptidase, a serine peptidase unrelated to trypsin and subtilisin, is implicated in memory disorders and is an important target of drug design. The catalytic competence of the Asp(641) residue of the catalytic triad (Ser(554), Asp(641), His(680)) was studied using the D641N and D641A variants of the enzyme. Both variants displayed 3 orders of magnitude reduction in k(cat)/K(m) for benzyloxycarbonyl-Gly-Pro-2-naphthylamide. Using an octapeptide substrate, the decrease was 6 orders of magnitude, whereas with Z-Gly-Pro-4-nitrophenyl ester there was virtually no change in k(cat)/K(m). This indicates that the contribution of Asp(641) is very much dependent on the substrate-leaving group, which was not the case for the classic serine peptidase, trypsin. The rate constant for benzyloxycarbonyl-Gly-Pro-thiobenzylester conformed to this series as demonstrated by a method designed for monitoring the hydrolysis of thiolesters in the presence of thiol groups. Alkylation of His(680) with Z-Gly-Pro-CH(2)Cl was concluded with similar rate constants for wild-type and D641A variant. However, kinetic measurements with Z-Gly-Pro-OH, a product-like inhibitor, indicated that the His(680) is not accessible in the enzyme variants. Crystal structure determination of these mutants revealed subtle perturbations related to the catalytic activity. Many of these observations show differences in the catalysis between trypsin and prolyl oligopeptidase. PubMed: 12228249DOI: 10.1074/jbc.M207386200 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.6 Å) |
Structure validation
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