THE CRYSTAL-STRUCTURES OF RECOMBINANT GLYCOSYLATED HUMAN RENIN ALONE AND IN COMPLEX WITH A TRANSITION-STATE ANALOG INHIBITOR

Recombinant human glycosylated renin has been crystallized in complex with CGP 38′560, a transition state analog inhibitor (IC50 = 2 × 10-9M), in a tetragonal crystal form. The structure has been determined to a resolution of 2.4 Å and refined to a crystallographic Rfactor of 17.6%. It reveals the conformation of the inhibitor as well as its interactions with the enzyme active site. The active site is a deep cleft between the N- and the C-terminal domains to which the inhibitor binds in an extended conformation filling the S4 to S2′ pockets. The structure of the complex is compared with that of the related uninhibited enzyme pepsin. Significant changes in the relative orientation of the N- and C-terminal domains are observed. In the inhibited renin structure the C-terminal loop segments forming the active site are closer to those from the N-terminal domain than in the related "open" pepsin structure. In addition, the structure of uninhibited glycosylated renin has been determined at 2.8 Å resolution from a cubic crystal form with two renin molecules in the asymmetric unit. The two independent renin molecules show different conformations with respect to the relative orientation of their N- and C-terminal domains; one molecule is found in the "closed inhibited" conformation, the other in the "open uninhibited" conformation. © 1991.