The structural and thermodynamic dissection of the interdomain cooperativity of human ACE

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The economic burden of cardiovascular illness is staggering, with estimated annual costs of £50 billion in the UK, Euro250 billion in the EU and $175 billion in the USA.Human somatic 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. The N- and C-domains of ACE display different substrate specificities.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 molecular structure of entire ACE and the design of 2nd generation of new 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 (with various clinically important inhibitors as well as novel domain selective inhibitors) using the technique X-ray crystallography have provided the platform for true structure-based design of better ACE inhibitors. This is a significant breakthrough in terms of the structural details of ACE and, more importantly, the mechanism of ACE inhibition. These important results pave the way for a more rigorous approach exploiting the differences between the domains through a structure based drug design route of novel domain-selective inhibitors. Thus the sustained effort on understanding the 'hidden' molecular properties of ACE has provided a firm platform for our group for new studies as outlined in our proposal.Our proposed experiments that builds on a body of previous and current work are directed at structural study of the full-length ACE. The proposal has its focus on the crucial structure-function studies of ACE addressing new and important biological questions which will have implications (in the longer term) for the design of new generation of selective inhibitors of ACE combining basic and translational research. The ultimate longer term aim will be the design of new compounds that are specific for the N- or C-terminal domain of ACE with the expectation that this will provide selective compounds with fewer side effects.