Analyses of ligand binding in five endothiapepsin crystal complexes and their use in the design and evaluation of novel renin inhibitors.
Five renin inhibitors were cocrystallized with endothiapepsin, a fungal enzyme homologous to renin. Crystal structures of inhibitor-bound complexes have provided invaluable insight regarding the three-dimensional structure of the aspartic proteinase family of enzymes, as well as the steric and polar interactions that occur between the proteins and the bound ligands. Beyond this, subtleties of binding have been revealed, including multiple subsite binding modes and subsite interdependencies. This information has been applied in the design of novel potent renin inhibitors and in the understanding of structure-activity relationships and enzyme selectivities.
Lunney
E A
EA
Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105-2430.
Hamilton
H W
HW
Hodges
J C
JC
Kaltenbronn
J S
JS
Repine
J T
JT
Badasso
M
M
Cooper
J B
JB
Dealwis
C
C
Wallace
B A
BA
Lowther
W T
WT
D000595:Amino Acid Sequence; D016282:Aspartic Acid Endopeptidases / Q000737:chemistry* / Q000378:metabolism*; D003198:Computer Simulation; D003460:Crystallization; D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D012083:Renin / Q000378:metabolism; D013329:Structure-Activity Relationship; D014867:Water / Q000378:metabolism; D000092502:Renin Inhibitors
D016282:Aspartic Acid Endopeptidases; D012083:Renin; D014867:Water; D000092502:Renin Inhibitors; C042466:Endothia aspartic proteinase