PDBsum entry 1o86

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Hydrolase/hydrolase inhibitor PDB id
Protein chain
575 a.a. *
_CL ×2
Waters ×570
* Residue conservation analysis

References listed in PDB file
Key reference
Title Crystal structure of the human angiotensin-Converting enzyme-Lisinopril complex.
Authors R.Natesh, S.L.Schwager, E.D.Sturrock, K.R.Acharya.
Ref. Nature, 2003, 421, 551-554. [DOI no: 10.1038/nature01370]
PubMed id 12540854
Angiotensin-converting enzyme (ACE) has a critical role in cardiovascular function by cleaving the carboxy terminal His-Leu dipeptide from angiotensin I to produce a potent vasopressor octapeptide, angiotensin II. Inhibitors of ACE are a first line of therapy for hypertension, heart failure, myocardial infarction and diabetic nephropathy. Notably, these inhibitors were developed without knowledge of the structure of human ACE, but were instead designed on the basis of an assumed mechanistic homology with carboxypeptidase A. Here we present the X-ray structure of human testicular ACE and its complex with one of the most widely used inhibitors, lisinopril (N2-[(S)-1-carboxy-3-phenylpropyl]-L-lysyl-L-proline; also known as Prinivil or Zestril), at 2.0 A resolution. Analysis of the three-dimensional structure of ACE shows that it bears little similarity to that of carboxypeptidase A, but instead resembles neurolysin and Pyrococcus furiosus carboxypeptidase--zinc metallopeptidases with no detectable sequence similarity to ACE. The structure provides an opportunity to design domain-selective ACE inhibitors that may exhibit new pharmacological profiles.
Figure 1.
Figure 1: Overview of tACE structure. a, Stereo view of the ribbon representation of the molecule looking down on the active site. The molecule can be divided into two portions, as subdomains I and II (cyan and pink, respectively). The active-site zinc ion and the lisinopril molecule are shown in green and yellow, respectively. The two chloride ions are shown as red spheres. b, Molecular surface representation (negative and positive potentials in red and blue, respectively) showing the active-site groove. The view is at 90 (towards the observer) to a. For clarity, the molecular surface has been sliced. The buried lisinopril molecule is shown in yellow. Helices 1, 2 and 3 forming the lid are shown. c, The structure -sequence relationship in tACE^10. The secondary structure elements (subdomain I in cyan; subdomain II in pink) follow the same colour code as in a. , -helices; , -strands; H, 3[10] helices. The important residues that are involved in binding are indicated as follows: zinc ligands, green boxes; chloride-binding residues, orange (Cl1) and red (Cl2) boxes; lisinopril-binding residues, yellow boxes; and glycosylation sites, black boxes.
Figure 2.
Figure 2: Details of the active site. a, Binding of lisinopril to tACE (stereo representation). Selected residues are shown in a 'ball-and-stick' representation with zinc atoms in green, chloride ions in red, water molecules in purple, and lisinopril (inhibitor) in yellow. Important secondary structure elements are marked. The lisinopril, Cl2, water hydrogen bonds and zinc coordination are shown in cyan, red, purple and green dotted lines, respectively. b, Schematic view of lisinopril binding with distances marked in . The different binding subsites are labelled.
The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (2003, 421, 551-554) copyright 2003.
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