Structural studies on human Angiotensin-I converting enzyme (ACE) and the design of novel domain specific inhibitors
Lead Research Organisation:
University of Bath
Department Name: Biology and Biochemistry
Abstract
Angiotensin-I converting enzyme [ACE, which contains two domains (N and C)] inhibitors are widely used to treat cardiovascular diseases, including high blood pressure, heart failure, coronary artery disease, fibrosis and kidney failure. However, current-generation ACE inhibitors, which were developed in the 1970?s and 1980?s, are hampered by common side effects. While there are many ACE inhibitors on the market that block both domains, there are no drugs that selectively inhibit the N domain and thereby accrue the advantages of reducing fibrosis and inflammation in the heart, kidney and lung, without the concomitant side effects induced by blockade of the C domain.. This underscores the importance of the determination of the 3D structure of ACE and the design of 2nd generation ACE-inhibitor complex/s that are safer and more effective. Our success in the determination of the crystal structure of human testis ACE (equivalent to the C domain of somatic ACE) and the N-domain of somatic ACE using X-ray crystallography have provided the platform for true structure-based design of ACE inhibitors. This is a significant breakthrough in terms of the structural biology of the protease and, more importantly, the mechanism of ACE inhibition. This paves the way for a more rigorous approach exploiting the differences between the domains through a structure based drug design approach of novel domain-selective inhibitors. Our proposed experiments are directed at structural study of the full-length somatic ACE and crystal structures of complexes of ACE with domain selective inhibitors combining basic and translational research on a important medical problem.
Technical Summary
Somatic angiotensin-I converting enzyme (ACE) - well known for its role in cardiovascular pathophysiology has an unusual, two-domain, double active-site structure. The two domains (designated N and C) are ~55% identical and each contains a similar active site with overlapping but distinct substrate preferences. While both convert angiotensin I to angiotensin II in vitro, current evidence suggests the C domain site predominates in this role in vivo. The N domain site inactivates a hemoregulatory and antifibrotic peptide, AcSDKP, in vivo. However, differences in the characteristics of the two domains may result in different context-dependent activities, as is the case with other enzymes containing tandem repeats. The N domain may also have a role in modulating C domain activity, through a combination of inter-domain cooperativity and structural stabilisation. Recent work on ACE active-site mutants containing one or more key residues replaced by their cognate residues from the other domain, synthesis of domain-selective inhibitors, and co-crystal structures of each domain with such inhibitors, has led to a better insight of the basis for domain selectivity and should enable the design of next-generation, domain-selective inhibitors with distinct pharmacological profiles. In addition, a recent report on the inactivation of the N-terminal catalytic site of ACE significantly reduces bleomycin-induced lung fibrosis and implicates AcSDKP in the mechanism of protection. This work makes a compelling case for the use of N-selective ACE inhibitors for increasing tolerance to bleomycin in cancer therapy and treatment of fibrosing lung diseases. In parallel, the proposed research would also help in better understanding the relationship between the structure and function of somatic ACE.
People |
ORCID iD |
| Ravi Acharya (Principal Investigator) |
Publications
Akif M
(2011)
Structural characterization of angiotensin I-converting enzyme in complex with a selenium analogue of captopril.
in The FEBS journal
Masuyer G
(2012)
Molecular recognition and regulation of human angiotensin-I converting enzyme (ACE) activity by natural inhibitory peptides.
in Scientific reports
Akif M
(2012)
Structural basis of peptide recognition by the angiotensin-1 converting enzyme homologue AnCE from Drosophila melanogaster.
in The FEBS journal
Anthony CS
(2012)
Structure based drug design of angiotensin-I converting enzyme inhibitors.
in Current medicinal chemistry
Harrison C
(2014)
ACE for all - a molecular perspective.
in Journal of cell communication and signaling
Douglas RG
(2014)
Fragment-based design for the development of N-domain-selective angiotensin-1-converting enzyme inhibitors.
in Clinical science (London, England : 1979)
Masuyer G
(2014)
Angiotensin-I converting enzyme (ACE): structure, biological roles, and molecular basis for chloride ion dependence.
in Biological chemistry
Michaud A
(2014)
Absence of cell surface expression of human ACE leads to perinatal death.
in Human molecular genetics
Kramer GJ
(2014)
Interkingdom pharmacology of Angiotensin-I converting enzyme inhibitor phosphonates produced by actinomycetes.
in ACS medicinal chemistry letters
Masuyer G
(2014)
Crystal structures of highly specific phosphinic tripeptide enantiomers in complex with the angiotensin-I converting enzyme.
in The FEBS journal
Yates CJ
(2014)
Molecular and thermodynamic mechanisms of the chloride-dependent human angiotensin-I-converting enzyme (ACE).
in The Journal of biological chemistry
Masuyer G
(2015)
Structural basis of Ac-SDKP hydrolysis by Angiotensin-I converting enzyme.
in Scientific reports
Harrison C
(2015)
A new high-resolution crystal structure of the Drosophila melanogaster angiotensin converting enzyme homologue, AnCE.
in FEBS open bio
Masuyer G
(2016)
Crystal structure of a peptidyl-dipeptidase K-26-DCP from Actinomycete in complex with its natural inhibitor.
in The FEBS journal
Larmuth KM
(2016)
Kinetic and structural characterization of amyloid-ß peptide hydrolysis by human angiotensin-1-converting enzyme.
in The FEBS journal
Fienberg S
(2018)
The Design and Development of a Potent and Selective Novel Diprolyl Derivative That Binds to the N-Domain of Angiotensin-I Converting Enzyme.
in Journal of medicinal chemistry
Abrie JA
(2018)
Investigation into the Mechanism of Homo- and Heterodimerization of Angiotensin-Converting Enzyme.
in Molecular pharmacology
Cozier GE
(2018)
Crystal structures of sampatrilat and sampatrilat-Asp in complex with human ACE - a molecular basis for domain selectivity.
in The FEBS journal
Cozier GE
(2018)
Molecular Basis for Multiple Omapatrilat Binding Sites within the ACE C-Domain: Implications for Drug Design.
in Journal of medicinal chemistry
Sturrock ED
(2019)
Structural basis for the C-domain-selective angiotensin-converting enzyme inhibition by bradykinin-potentiating peptide b (BPPb).
in The Biochemical journal
| Title | Deposition of Structural data with Protein Data Bank |
| Description | X-ray diffraction data and Atomic coordinates of reported structures |
| Type Of Material | Biological samples |
| Provided To Others? | No |
| Impact | The structural data are made available in the public domain. This will be useful for structure-based-drug-design research on Angiotensin-1 converting enzyme aimed at cardivascular diseases. |
| Description | Academic collaboration |
| Organisation | College of France |
| Department | Centre for Interdisciplinary Research in Biology |
| Country | France |
| Sector | Academic/University |
| PI Contribution | Professor Ravi Acharya's group (Bath) - Structural Biology |
| Collaborator Contribution | Professor Edward Sturrock's group (Cape Town, Soth Africa) - Biochemistry Profoessor Elwyn Isaac's group (Leeds, UK) - Enzymology Professor Pierre Corvol's group (Paris, France) - Medical Biochemistry Dr. Vincent Dive (CEA, France)- Medicinal Chemistry |
| Impact | Outcome - Peer-Reviewed Research publications Multi-disciplinary collaboration |
| Description | Academic collaboration |
| Organisation | Saclay Nuclear Research Centre |
| Department | Service d’Ingénierie Moléculaire des Protéines (SIMOPRO) |
| Country | France |
| Sector | Academic/University |
| PI Contribution | Professor Ravi Acharya's group (Bath) - Structural Biology |
| Collaborator Contribution | Professor Edward Sturrock's group (Cape Town, Soth Africa) - Biochemistry Profoessor Elwyn Isaac's group (Leeds, UK) - Enzymology Professor Pierre Corvol's group (Paris, France) - Medical Biochemistry Dr. Vincent Dive (CEA, France)- Medicinal Chemistry |
| Impact | Outcome - Peer-Reviewed Research publications Multi-disciplinary collaboration |
| Description | Academic collaboration |
| Organisation | University of Cape Town |
| Department | Institute of Infectious Disease and Molecular Medicine (IIDMM) |
| Country | South Africa |
| Sector | Academic/University |
| PI Contribution | Professor Ravi Acharya's group (Bath) - Structural Biology |
| Collaborator Contribution | Professor Edward Sturrock's group (Cape Town, Soth Africa) - Biochemistry Profoessor Elwyn Isaac's group (Leeds, UK) - Enzymology Professor Pierre Corvol's group (Paris, France) - Medical Biochemistry Dr. Vincent Dive (CEA, France)- Medicinal Chemistry |
| Impact | Outcome - Peer-Reviewed Research publications Multi-disciplinary collaboration |
| Description | Academic collaboration |
| Organisation | University of Leeds |
| Department | School of Biology |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Professor Ravi Acharya's group (Bath) - Structural Biology |
| Collaborator Contribution | Professor Edward Sturrock's group (Cape Town, Soth Africa) - Biochemistry Profoessor Elwyn Isaac's group (Leeds, UK) - Enzymology Professor Pierre Corvol's group (Paris, France) - Medical Biochemistry Dr. Vincent Dive (CEA, France)- Medicinal Chemistry |
| Impact | Outcome - Peer-Reviewed Research publications Multi-disciplinary collaboration |