文摘
Angiotensin I-converting enzyme (ACE) is central to the regulation of the renin-angiotensinsystem 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 nowunderstood that these domains function differently in vivo. The recently solved crystal structures of bothdomains (N and C) open the door to new domain-specific inhibitor design, taking advantage of thedifferences between these two large active sites. Here we present the first crystal structure at a resolutionof 2.25 Å of testis ACE (identical to the C domain of somatic ACE) with the highly C-domain-specificphosphinic inhibitor, RXPA380. Testis ACE retains the same conformation as seen in previously determinedinhibitor complexes, but the RXPA380 central backbone conformation is more similar to that seen for theinhibitor captopril than enalaprilat. The RXPA380 molecule occupies more subsites of the testis ACEactive 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 explainedby 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 siteand the binding of a potent C-domain-selective inhibitor provide the first structural data for the design oftruly domain-specific pharmacophores.
