9RVA

Crystal structure of the extracellular part of human ACE2 in complex with the macrocyclic peptide WJL-63

Summary for 9RVA

• Entry DOI: 10.2210/pdb9rva/pdb
• Descriptor: Angiotensin-converting enzyme 2, NONAETHYLENE GLYCOL, macrocyclic peptide WJL-63, ... (11 entities in total)
• Functional Keywords: sars-cov-2 receptor; raas protective path; enzyme, peptide binding protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 90121.72

Authors

Benoit, R.M.,Rodrigues, M.J.,Wieser, M.M. (deposition date: 2025-07-07, release date: 2026-05-06, Last modification date: 2026-05-20)

Primary citation

Benoit, R.M.,Wang, J.,Beyer, D.,Abbas, A.,Rodrigues, M.J.,Wieser, M.M.,Deupi, X.,Muller, C.,Suga, H.,Bode, J.W.
Development and structure-guided characterization of a novel ACE2-binding macrocyclic peptide.
J Struct Biol X, 13:100145-100145, 2026

PubMed Abstract: Angiotensin-converting enzyme 2 (ACE2) is a key node in the protective axis of the renin-angiotensin-aldosterone system (RAAS) for blood pressure and hydroelectrolyte regulation and the receptor recognized by the spike glycoproteins of the severe acute respiratory syndrome (SARS) coronaviruses (CoV) SARS-CoV and SARS-CoV-2. We identified the macrocyclic peptide WJL-63 by mRNA display and characterized it biochemically and with respect to ACE2-binding. The crystal structure of the extracellular region of ACE2 in complex with the peptide at 2.2 Å resolution was elucidated. The structure revealed a binding mode in which WJL-63 is accommodated towards one side of the catalytic cleft of the peptidase domain, without contacting the conserved zinc ion site. WJL-63 residues Q4, R7, R11, and R14 anchor the peptide in the binding pocket. The peptide contacts both peptidase subdomains. The upright binding mode requires an open ACE2 conformation, in contrast to small-molecule carboxypeptidase inhibitors, which typically bind to the closed conformation. One side of WJL-63 is accessible for modification such as the herein reported conjugation of a chelator for radiometal labeling. The radiolabeled DOTA-WJL-63 was evaluated on ACE2-transfected HEK cells, where it exhibited binding with a K value of 90 ± 28 nM. The ACE2 - WJL-63 complex structure provides a basis for the development of compounds that modulate ACE2 conformation and for the development of imaging agents for visualization of ACE2, including fluorescence or electron microscopy and positron emission tomography (PET).

PubMed: 42095196
DOI: 10.1016/j.yjsbx.2026.100145

Experimental method

X-RAY DIFFRACTION (2.2 Å)