Crystal structure of the human angiotensin-converting enzyme-lisinopril complex
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, myocard...
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| Veröffentlicht in: | Nature (London) 2003-01, Vol.421 (6922), p.551-554 |
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| description | 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 Å 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. |
| doi_str_mv | 10.1038/nature01370 |
| format | Article |
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Ravi ; Natesh, Ramanathan ; Schwager, Sylva L. U</creator><creatorcontrib>Sturrock, Edward D ; Acharya, K. Ravi ; Natesh, Ramanathan ; Schwager, Sylva L. U</creatorcontrib><description>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 Å 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.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/nature01370</identifier><identifier>PMID: 12540854</identifier><identifier>CODEN: NATUAS</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Amino Acid Sequence ; Angiotensin-Converting Enzyme Inhibitors - chemistry ; Angiotensin-Converting Enzyme Inhibitors - metabolism ; Antihypertensive agents ; Binding Sites ; Biological and medical sciences ; Carboxypeptidases - chemistry ; Carboxypeptidases - metabolism ; Cardiovascular system ; Crystallography, X-Ray ; Crystals ; Drug Design ; Enzymes ; Heart ; Humanities and Social Sciences ; Humans ; Hypertension ; Inhibitors ; letter ; Lisinopril - chemistry ; Lisinopril - metabolism ; Male ; Medical sciences ; Metalloendopeptidases - chemistry ; Metalloendopeptidases - metabolism ; Models, Molecular ; Molecular Sequence Data ; multidisciplinary ; Myocardial infarction ; Peptidyl-Dipeptidase A - chemistry ; Peptidyl-Dipeptidase A - metabolism ; Pharmacology ; Pharmacology. 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Jan 30, 2003</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c677t-ee1b487186a204b2184f5845dbb6ba7d835a341e770d475389d148522ed7e153</citedby><cites>FETCH-LOGICAL-c677t-ee1b487186a204b2184f5845dbb6ba7d835a341e770d475389d148522ed7e153</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,2727,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=14698846$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12540854$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sturrock, Edward D</creatorcontrib><creatorcontrib>Acharya, K. Ravi</creatorcontrib><creatorcontrib>Natesh, Ramanathan</creatorcontrib><creatorcontrib>Schwager, Sylva L. U</creatorcontrib><title>Crystal structure of the human angiotensin-converting enzyme-lisinopril complex</title><title>Nature (London)</title><addtitle>Nature</addtitle><addtitle>Nature</addtitle><description>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 Å 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.</description><subject>Amino Acid Sequence</subject><subject>Angiotensin-Converting Enzyme Inhibitors - chemistry</subject><subject>Angiotensin-Converting Enzyme Inhibitors - metabolism</subject><subject>Antihypertensive agents</subject><subject>Binding Sites</subject><subject>Biological and medical sciences</subject><subject>Carboxypeptidases - chemistry</subject><subject>Carboxypeptidases - metabolism</subject><subject>Cardiovascular system</subject><subject>Crystallography, X-Ray</subject><subject>Crystals</subject><subject>Drug Design</subject><subject>Enzymes</subject><subject>Heart</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Hypertension</subject><subject>Inhibitors</subject><subject>letter</subject><subject>Lisinopril - chemistry</subject><subject>Lisinopril - metabolism</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Metalloendopeptidases - chemistry</subject><subject>Metalloendopeptidases - metabolism</subject><subject>Models, Molecular</subject><subject>Molecular Sequence Data</subject><subject>multidisciplinary</subject><subject>Myocardial infarction</subject><subject>Peptidyl-Dipeptidase A - chemistry</subject><subject>Peptidyl-Dipeptidase A - metabolism</subject><subject>Pharmacology</subject><subject>Pharmacology. 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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 Å 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.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>12540854</pmid><doi>10.1038/nature01370</doi><tpages>4</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
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| ispartof | Nature (London), 2003-01, Vol.421 (6922), p.551-554 |
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| language | eng |
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| subjects | Amino Acid Sequence Angiotensin-Converting Enzyme Inhibitors - chemistry Angiotensin-Converting Enzyme Inhibitors - metabolism Antihypertensive agents Binding Sites Biological and medical sciences Carboxypeptidases - chemistry Carboxypeptidases - metabolism Cardiovascular system Crystallography, X-Ray Crystals Drug Design Enzymes Heart Humanities and Social Sciences Humans Hypertension Inhibitors letter Lisinopril - chemistry Lisinopril - metabolism Male Medical sciences Metalloendopeptidases - chemistry Metalloendopeptidases - metabolism Models, Molecular Molecular Sequence Data multidisciplinary Myocardial infarction Peptidyl-Dipeptidase A - chemistry Peptidyl-Dipeptidase A - metabolism Pharmacology Pharmacology. Drug treatments Protein Conformation Pyrococcus furiosus - enzymology Science Science (multidisciplinary) Substrate Specificity |
| title | Crystal structure of the human angiotensin-converting enzyme-lisinopril complex |
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