Models for the three-dimensional structure of renin inhibitors bound in the active site of human renin: an analysis of the properties that produce tight binding.
Three-dimensional models of the octapeptide segment of renin substrate and of several inhibitors characterized by a modified scissile bond were constructed at the active site of human renin. The substrate and inhibitor models were based on the structure of pepstatin solved by x-ray crystallography to a resolution of 1.8 A. The renin structure, previously reported by us, was based on the structures of homologous aspartyl proteases solved by x-ray diffraction techniques to a resolution of 2.1 A or higher. An energy minimization program, CHARMM, was used to refine these structures with respect to the optimal interaction of the enzyme and its inhibitor, and to calculate the energy of each inhibitor-enzyme interaction. The results indicate that the most significant difference between the binding of inhibitors and of the natural substrate is caused by a reduction in electrostatic rather than conformational strain.
Carlson
W D
WD
Cardiac Unit, Massachusetts General Hospital, Boston 02114.
Handschumacher
M
M
Summers
N
N
Karplus
M
M
Haber
E
E
D001665:Binding Sites / Q000187:drug effects; D003461:Crystallography; D006801:Humans; D008956:Models, Chemical; D011487:Protein Conformation; D012083:Renin / Q000737:chemistry; D014961:X-Ray Diffraction; D000092502:Renin Inhibitors
D012083:Renin; D000092502:Renin Inhibitors