X-ray studies of aspartic proteinase-statine inhibitor complexes.
The conformation of a statine-containing renin inhibitor complexed with the aspartic proteinase from the fungus Endothia parasitica (EC 3.4.23.6) has been determined by X-ray diffraction at 2.2-A resolution (R = 0.17). We describe the structure of the complex at high resolution and compare this with a 3.0-A resolution analysis of a bound inhibitor, L-364,099, containing a cyclohexylalanine analogue of statine. The inhibitors bind in extended conformations in the long active-site cleft, and the hydroxyl of the transition-state analogue, statine, interacts strongly with the catalytic aspartates via hydrogen bonds to the essential carboxyl groups. This work provides a detailed structural analysis of the role of statine in peptide inhibitors. It shows conclusively that statine should be considered a dipeptide analogue (occupying P1 to P1') despite lacking the equivalent of a P1' side chain, although other inhibitor residues (especially P2) may compensate by interacting at the unoccupied S1' specificity subsite.
Cooper
J B
JB
Department of Crystallography, Birkbeck College, London, U.K.
Foundling
S I
SI
Blundell
T L
TL
Boger
J
J
Jupp
R A
RA
Kay
J
J
D000596:Amino Acids / Q000378:metabolism*; D001203:Ascomycota / Q000201:enzymology*; D016282:Aspartic Acid Endopeptidases; D001665:Binding Sites; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D006860:Hydrogen Bonding; D009097:Multienzyme Complexes; D011487:Protein Conformation; D013696:Temperature; D014961:X-Ray Diffraction; D000092502:Renin Inhibitors
D000596:Amino Acids; D016282:Aspartic Acid Endopeptidases; D010450:Endopeptidases; D009097:Multienzyme Complexes; D000092502:Renin Inhibitors; C013165:statine