Structural basis for the C-domain selective angiotensin converting enzyme inhibition by bradykinin-potentiating peptide b (BPPb).

We present the BPPb-N-domain structure in comparison with the previously reported BPPb-C-domain structure and highlight key differences in peptide interactions with the S4 to S9 subsites. This suggests involvement of these subsites in conferring C-domain selective BPPb binding, in agreement with the mutagenesis results where unique residues governing differences in active site exposure, lid structure and dynamics between the two domains were the major drivers for C-domain selective BPPb binding.  Mere disruption of BPPb interactions with unique S2 and S4 subsite residues, which synergistically assist in BPPb binding, was insufficient to abolish C-domain selectivity. The combination of unique S9-S4 and S2' subsite C-domain residues were required for the favourable entry, orientation and thus, selective binding of the peptide.  This emphasizes the need to consider factors other than direct protein-inhibitor interactions to guide the design of domain-selective ACE inhibitors, especially in the case of larger peptides. PMID: 31072910 [PubMed - as supplied by publisher]
Source: The Biochemical Journal - Category: Biochemistry Authors: Tags: Biochem J Source Type: research