Browsing by Author "Chitapi, Itai"

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    The structure of testis angiotensin-converting enzyme (tACE-g13) in complex with the inhibitor RXPA380
    (2006) Chitapi, Itai; Sewell, Bryan Trevor; Sturrock, E D
    Angiotensin-converting enzyme (ACE), a zinc metalloprotease, is a key regulator of the mammalian renin-angiotensin system (RAS) Primarily, ACF is a dipeptidl peptidase which cleaves angiotensin I to produce angiotensin II, a potent vasoconstrictor. By the same enzymatic mechanism, ACE also inactivates the vasodilator bradykinin. The main overall effect of these actions is an increase in blood pressure. Several ACF inhibitors have been developed as drugs for the treatment of myocardial infarction, hypertension, kidney failure and heart failure.
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    The structure of testis angiotensin-converting enzyme in complex with the C domain-specific inhibitor RXPA380
    (American Chemical Society, 2007) Corradi, Hazel R; Chitapi, Itai; Sewell, B Trevor; Georgiadis, Dimitris; Dive, Vincent; Sturrock, Edward D; Acharya, K Ravi
    Angiotensin I-converting enzyme (ACE) is central to the regulation of the renin−angiotensin system and is a key therapeutic target for combating hypertension and related cardiovascular diseases. Currently available drugs bind both active sites of its two homologous domains, although it is now understood that these domains function differently in vivo. The recently solved crystal structures of both domains (N and C) open the door to new domain-specific inhibitor design, taking advantage of the differences between these two large active sites. Here we present the first crystal structure at a resolution of 2.25 Å of testis ACE (identical to the C domain of somatic ACE) with the highly C-domain-specific phosphinic inhibitor, RXPA380. Testis ACE retains the same conformation as seen in previously determined inhibitor complexes, but the RXPA380 central backbone conformation is more similar to that seen for the inhibitor captopril than enalaprilat. The RXPA380 molecule occupies more subsites of the testis ACE active site than the previously determined inhibitors and possesses bulky moieties that extend into the S2‘ and S2 subsites. Thus the high affinity of RXPA380 for the testis ACE/somatic ACE C domain is explained by the interaction of these bulky moieties with residues unique to these domains, specifically Phe 391, Val 379, and Val 380, that are not found in the N domain. The characterization of the extended active site and the binding of a potent C-domain-selective inhibitor provide the first structural data for the design of truly domain-specific pharmacophores.
  • Thumbnail Image
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    Open Access
    The structure of testis angiotensin-converting enzyme in complex with the C domain-specific inhibitor RXPA380.
    (American Chemical Society, 2007) Corradi, Hazel R; Chitapi, Itai; Sewell, Trevor B; Georgiadis, Dimitris; Dive, Vincent; Sturrock, Edward D; Acharya, Ravi K
    Angiotensin I-converting enzyme (ACE) is central to the regulation of the renin-angiotensin system and is a key therapeutic target for combating hypertension and related cardiovascular diseases. Currently available drugs bind both active sites of its two homologous domains, although it is now understood that these domains function differently in vivo. The recently solved crystal structures of both domains (N and C) open the door to new domain-specific inhibitor design, taking advantage of the differences between these two large active sites. Here we present the first crystal structure at a resolution of 2.25 Å of testis ACE (identical to the C domain of somatic ACE) with the highly C-domain-specific phosphinic inhibitor, RXPA380. Testis ACE retains the same conformation as seen in previously determined inhibitor complexes, but the RXPA380 central backbone conformation is more similar to that seen for the inhibitor captopril than enalaprilat. The RXPA380 molecule occupies more subsites of the testis ACE active site than the previously determined inhibitors and possesses bulky moieties that extend into the S2′ and S2 subsites. Thus the high affinity of RXPA380 for the testis ACE/somatic ACE C domain is explained by the interaction of these bulky moieties with residues unique to these domains, specifically Phe 391, Val 379, and Val 380, that are not found in the N domain. The characterization of the extended active site and the binding of a potent C-domain-selective inhibitor provide the first structural data for the design of truly domain-specific pharmacophores.