Background: The Angiotensin-I converting enzyme (ACE) is one of the most important
components of the renin-angiotensin-aldosterone system controlling blood pressure and renal functions.
Inhibitors of ACE are first line therapeutics used in the treatment of hypertension and related
cardiovascular diseases. Somatic ACE consists of two homologous catalytic domains, the C- and
N-domains. Recent findings have shown that although both domains are highly homologous in
structure, they may have different physiological functions. The C-domain is primarily involved in
the control of blood pressure, in contrast to the N-domain that is engaged in the regulation of hematopoietic
stem cell proliferation. The currently available ACE inhibitors have some adverse effects
that can be attributed to the non-selective inhibition of both domains. In addition, specific Ndomain
inhibitors have emerged as potential antifibrotic drugs. Therefore, ACE is still an important
drug target for the development of novel domain-selective drugs not only for the cardiovascular
system but also for other systems.
Objective: Detailed structural information about interactions in the protein-ligand complex is crucial
for rational drug design. This review highlights the structural information available from crystallographic
data which is essential for the development of domain selective inhibitors of ACE.
Methods: Over eighty crystal complexes of ACE are placed into the Protein Database. An overview
of X-ray ACE complexes with various inhibitors in C- and N-domains and an analysis of
their binding mode have given mechanistic explanation of the structural determinants of selective
ligand binding. In addition, ACE domain selective inhibitors with dual modes of action in complexes
with ACE are also discussed.
Conclusion: Selectivity of ACE inhibitors for the N- and C-domain is controlled by subtle differences
in the amino-acids forming the active site. Reported studies of crystal complexes of inhibitors
in the C- and N-domains revealed that most selective inhibitors interact with non-conserved
amino-acids between domains and have distinct interactions with the residues in the S2 and S2’
subsites of the ACE catalytic site. Moreover, unusual binding of the second molecule of inhibitors
in the binding cavity opens new possibilities of exploiting more distant regions of the catalytic
center in structure-based design of novel drugs.