Angiotensin‐converting enzyme open for business: structural insights into the subdomain dynamics
| Autor: | Gyles E. Cozier, Edward D. Sturrock, K. Ravi Acharya, Lizelle Lubbe |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
metalloprotease Protein Conformation Stereochemistry Protein Data Bank (RCSB PDB) Angiotensin-Converting Enzyme Inhibitors angiotensin‐1‐converting enzyme Peptide Peptidyl-Dipeptidase A X‐ray crystallography Crystallography X-Ray Biochemistry Substrate Specificity 03 medical and health sciences 0302 clinical medicine Catalytic Domain Humans enzyme mechanism Binding site Databases Protein domain dynamics Molecular Biology chemistry.chemical_classification Binding Sites biology Chemistry C-terminus Angiotensin-converting enzyme Original Articles Cell Biology computer.file_format Protein Data Bank Enzyme structure Endopeptidase enzyme structure 030104 developmental biology 030220 oncology & carcinogenesis biology.protein Original Article computer Protein Binding |
| Zdroj: | The Febs Journal |
| ISSN: | 1742-4658 1742-464X |
| DOI: | 10.1111/febs.15601 |
| Popis: | Angiotensin‐1‐converting enzyme (ACE) is a key enzyme in the renin–angiotensin–aldosterone and kinin systems where it cleaves angiotensin I and bradykinin peptides, respectively. However, ACE also participates in numerous other physiological functions, can hydrolyse many peptide substrates and has various exo‐ and endopeptidase activities. ACE achieves this complexity by containing two homologous catalytic domains (N‐ and C‐domains), which exhibit different substrate specificities. Here, we present the first open conformation structures of ACE N‐domain and a unique closed C‐domain structure (2.0 Å) where the C terminus of a symmetry‐related molecule is observed inserted into the active‐site cavity and binding to the zinc ion. The open native N‐domain structure (1.85 Å) enables comparison with ACE2, a homologue previously observed in open and closed states. An open S2_S′‐mutant N‐domain structure (2.80 Å) includes mutated residues in the S2 and S′ subsites that effect ligand binding, but are distal to the binding site. Analysis of these structures provides important insights into how structural features of the ACE domains are able to accommodate the wide variety of substrates and allow different peptidase activities. Database The atomic coordinates and structure factors for Open nACE, Open S2_S′‐nACE and Native G13‐cACE structures have been deposited with codes 6ZPQ, 6ZPT and 6ZPU, respectively, in the RCSB Protein Data Bank, www.pdb.org Angiotensin‐1‐converting enzyme (ACE) has broad substrate specificity and physiological functions. The first open structure of ACE N‐domain (nACE) presented here shows similar domain opening as ACE2 (close ACE homologue) that allows substrates to bind, and suggests extended binding site for endopeptidase activity. A second mutant nACE open structure examines the role of distal residues on ligand binding. In addition, a novel ACE C‐domain structure explains long peptide substrate binding. |
| Databáze: | OpenAIRE |
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