ELUCIDATION OF THE CAUSE FOR REDUCED ACTIVITY OF ABNORMAL HUMAN PLASMIN CONTAINING AN ALA(55)-THR MUTATION - IMPORTANCE OF HIGHLY CONSERVEDALA(55) IN SERINE PROTEASES

In serine proteases, Ala(55) is highly conserved and located just behi nd the catalytic triad, That the activity of human plasmin is reduced by the A55T substitution indicates the importance of Ala(55) in cataly sis. In the present study, the 3-D model of A55T human plasmin shows t hat an unusual hydrogen bond between Thr(55) O gamma 1 and His(57) N e psilon 2 alters His(57) into an inactive conformation in which His(57) cannot accept a proton from Ser(195) as a catalytic base. Our results demonstrate that Ala(55) contributes heavily to the active conformati on of His(57) and ensures the proton transfer from Ser(195) to His(57) . (C) 1998 Federation of European Biochemical Societies.