6QS1

Crystal structure of human Angiotensin-1 converting enzyme N-domain in complex with BPPb

Summary for 6QS1

• Entry DOI: 10.2210/pdb6qs1/pdb
• Descriptor: Angiotensin-converting enzyme, BORIC ACID, TRIETHYLENE GLYCOL, ... (16 entities in total)
• Functional Keywords: angiotensin-1 converting enzyme, ace inhibitor, bradykinin potentiating peptide, vasopeptidase inhibitor, hydrolase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 152628.27

Authors

Cozier, G.E.,Acharya, K.R. (deposition date: 2019-02-20, release date: 2019-05-22, Last modification date: 2024-11-13)

Primary citation

Sturrock, E.D.,Lubbe, L.,Cozier, G.E.,Schwager, S.L.U.,Arowolo, A.T.,Arendse, L.B.,Belcher, E.,Acharya, K.R.
Structural basis for the C-domain-selective angiotensin-converting enzyme inhibition by bradykinin-potentiating peptide b (BPPb).
Biochem.J., 476:1553-1570, 2019

PubMed Abstract: Angiotensin-converting enzyme (ACE) is a zinc metalloprotease best known for its role in blood pressure regulation. ACE consists of two homologous catalytic domains, the N- and C-domain, that display distinct but overlapping catalytic functions owing to subtle differences in substrate specificity. While current generation ACE inhibitors target both ACE domains, domain-selective ACE inhibitors may be clinically advantageous, either reducing side effects or having utility in new indications. Here, we used site-directed mutagenesis, an ACE chimera and X-ray crystallography to unveil the molecular basis for C-domain-selective ACE inhibition by the bradykinin-potentiating peptide b (BPPb), naturally present in Brazilian pit viper venom. 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 S to S subsites. This suggests the 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 S and S subsite residues, which synergistically assist in BPPb binding, was insufficient to abolish C-domain selectivity. The combination of unique S-S and S' subsite C-domain residues was 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.

PubMed: 31072910
DOI: 10.1042/BCJ20190290

Experimental method

X-RAY DIFFRACTION (1.8 Å)