Title : Crystal structure of the N
domain of human somatic
angiotensin I-converting enzyme provides a structural basis for domain-specific inhibitor design
Abstract :
- Human somatic angiotensin I-converting enzyme ( sACE ) is a key regulator of blood pressure and an important drug target for combating cardiovascular and renal disease
- sACE comprises two homologous metallopeptidase domains , N and C, joined by an inter-domain linker
- Both domains are capable of cleaving the two hemoregulatory peptides angiotensin I and bradykinin , but differ in their affinities for a range of other substrates and inhibitors
- Previously we determined the structure of testis ACE (C domain ); here we present the crystal structure of the N domain of sACE (both in the presence and absence of the antihypertensive drug lisinopril) in order to aid the understanding of how these two domains differ in specificity and function
- In addition, the structure of most of the inter-domain linker allows us to propose relative domain positions for sACE that may contribute to the domain cooperativity
- The structure now provides a platform for the design of "domain-specific" second-generation ACE inhibitors