Three-dimensional molecular modeling explains why catalytic function for angiotensin-I is different between human and rat chymases.
Although angiotensin (ANG)-I is a substrate sensitive to chymase, the cleavage site differs among the chymase families. While human chymase (HC) hydrolyses the Phe8-His9 bond of ANG-I to ANG-II, rat chymase (RMCP-I) degrades the Tyr4-Ile5 bond of ANG-I to the inactive fragments. To clarify this different catalysis for ANG-I at the atomic level, three-dimensional structures of HC and RMCP-I were constructed by the molecular dynamic simulation. The energy-refined models clearly showed the significant difference in the electrostatic potential of the solvent surface. From the modeling study of their complex structures with ANG-I, the functional difference between both enzymes was clearly related with the electrostatic difference, especially at the C-terminal substrate-binding site.
Yamamoto
D
D
Medical Computation Center, Osaka Medical College, Japan.
Shiota
N
N
Takai
S
S
Ishida
T
T
Okunishi
H
H
Miyazaki
M
M
D000595:Amino Acid Sequence; D000803:Angiotensin I / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D053818:Chymases; D003198:Computer Simulation; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D051381:Rats; D017386:Sequence Homology, Amino Acid; D012697:Serine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D013045:Species Specificity; D013379:Substrate Specificity
D000803:Angiotensin I; D012697:Serine Endopeptidases; D053818:Chymases