9RVT

ACE2 extracellular domain in complex with the macrocyclic peptide GR1.4

Summary for 9RVT

• Entry DOI: 10.2210/pdb9rvt/pdb
• Descriptor: Processed angiotensin-converting enzyme 2, macrocyclic peptide GR1.4 (3 entities in total)
• Functional Keywords: hydrolase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 8
• Total formula weight: 288295.60

Authors

Brear, P.,Hyvonen, M. (deposition date: 2025-07-08, release date: 2026-04-08)

Primary citation

Romanyuk, Z.,Bettin, G.,Brear, P.,Linciano, S.,Mazzocato, Y.,Bonadies, S.,Zanotto, I.,Mazzucco, C.,Monferone, A.,Soler, M.A.,Pasut, G.,Martin, S.,Scarso, A.,Heinis, C.,Rothenberger, S.,Hyvonen, M.,Angelini, A.
Yeast Display Technology Enables Rapid Discovery of Low-Nanomolar Macrocyclic Peptide Inhibitors of Human Angiotensin-Converting Enzyme 2.
J.Med.Chem., 2026

PubMed Abstract: Macrocyclic peptides (MPs) are valuable molecular formats for drug development, bridging small molecules and larger biologics due to their favorable pharmacological properties. Here, we describe the discovery of low-nanomolar inhibitors of human angiotensin-converting enzyme 2 (hACE2) by quantitatively screening millions of structurally diverse disulfide-cyclized peptide ligands using yeast display technology. The most potent yeast-encoded "one-ring" and "two-ring" MP inhibit hACE2 with values of 1.9 and 1.5 nM, respectively. These inhibitory potencies are comparable to those of other cyclic peptides discovered using well-established display technologies. Crystal structures of the two MPs in complex with hACE2 reveal the adoption of either a rigid β-hairpin or a cysteine-stabilized α-helix/α-helix motif. Both MPs exhibit binding modes distinct from those of previously reported inhibitors. Thus, yeast display is a valid technology to rapidly generate MPs with desired binding properties for the development of potential therapeutics.

PubMed: 41875055
DOI: 10.1021/acs.jmedchem.5c02876

Experimental method

X-RAY DIFFRACTION (2.39 Å)