THE 1.8 ANGSTROM CRYSTAL-STRUCTURE OF HUMAN CATHEPSIN-G IN COMPLEX WITH SUC-VAL-PRO-PHE(P)-(OPH)(2) - A JANUS-FACED PROTEINASE WITH 2 OPPOSITE SPECIFICITIES

The crystal structure of human neutrophil cathepsin G, complexed with the peptidyl phosphonate inhibitor Suc-Val-Pro-Phe(P)-(OPh)(2), has be en determined to a resolution of 1.8 Angstrom using Patterson search t echniques, The cathepsin G structure shows the polypeptide fold charac teristic of trypsin-like serine proteinases and is especially similar to rat mast cell proteinase II, Unique to cathepsin G, however, is the presence of Glu226 (chymotrypsinogen numbering), which is situated at the bottom of the S1 specificity pocket, dividing it into two compart ments, For this reason, the benzyl side chain of the inhibitor Phe(P) residue does not fully occupy the pocket but is, instead, located at i ts entrance, Its positively charged equatorial edge is involved in a f avourable electrostatic interaction with the negatively charged carbox ylate group of Glu226, Arrangement of this Glu226 carboxylate would al so allow accommodation of a Lys side chain in this S1 pocket, in agree ment with the recently observed cathepsin G preference for Lys and Phe at P1, The cathepsin G complex with the covalently bound phosphonate inhibitor mimics a tetrahedral substrate intermediate, A comparison of the Arg surface distributions of cathepsin G, leukocyte elastase and rat mast cell protease II shows no simple common recognition pattern f or a mannose-6-phosphate receptor-independent targeting mechanism for sorting of these granular proteinases.