Structural basis of the lisinopril-binding specificity in N- and C-domains of human somatic ACE.
Angiotensin I-converting enzyme (ACE) is a dipeptidyl carboxypeptidase which converts angiotensin I into the vasopressor peptide angiotensin II and also inactivates the hypotensive peptide bradykinin, playing an important role in blood pressure regulation. The present work describes the molecular modeling of the N-terminal human somatic ACE in complex with the inhibitor lisinopril, identifying the residues involved in the inhibitor-binding pocket. The obtained results identify differences in the lisinopril lysine moiety-binding residues for N- and C-terminals of sACE domains and an important carboxy-terminal proline hydrophobic accommodations mediated by the aromatic ring of Tyr532 and Tyr1128 residues, respectively. The present model will be useful for the development of a new inhibitor family based on the natural BPP peptides and derivatives, or even to improve the binding capacities and the domain specificity of the already known inhibitors.
Fernandez
Jorge H
JH
Center of Applied Toxinology, Instituto Butantan, SP, Brazil.
Hayashi
Mirian A F
MA
Camargo
Antonio C M
AC
Neshich
Goran
G
D000595:Amino Acid Sequence; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000378:metabolism*; D020134:Catalytic Domain / Q000235:genetics; D002712:Chlorides / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D017706:Lisinopril / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D007703:Peptidyl-Dipeptidase A / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity
D000806:Angiotensin-Converting Enzyme Inhibitors; D002712:Chlorides; D017706:Lisinopril; D007703:Peptidyl-Dipeptidase A