9R19

Crystal structure of human ACE2 in complex with VHH B07 and VHH B10

Summary for 9R19

• Entry DOI: 10.2210/pdb9r19/pdb
• Descriptor: Processed angiotensin-converting enzyme 2, VHH B10, VHH B07, ... (6 entities in total)
• Functional Keywords: human ace2, vhh, structural protein, hydrolase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 9
• Total formula weight: 309034.84

Authors

Blachier, S.,Vaney, M.C.,Fernandez, I.,Arbabian, A.,Rey, F.A.R.,Haouz, A.,Brelot, A. (deposition date: 2025-04-25, release date: 2025-09-17, Last modification date: 2026-04-01)

Primary citation

Blachier, S.,Vaney, M.C.,Conquet, L.,Staropoli, I.,Fernandez, I.,Giraud, E.,Arbabian, A.,Michel, V.,Szilagyi, F.,Guez, S.,Boucharlat, A.,Chiaravalli, J.,Tran-Rajau, J.,Dufour, E.,Haouz, A.,Petres, S.,Planas, D.,Montagutelli, X.,Agou, F.,Lafaye, P.,Ayme, G.,Schwartz, O.,Rey, F.A.,Enninga, J.,Brelot, A.
Targeting ACE2 with a camelid antibody inhibits SARS-CoV-2 binding and has protective effects in vivo.
Nat Commun, 16:10268-10268, 2025

PubMed Abstract: The continuous emergence of antibody-escape variants of SARS-CoV-2 demands the identification of alternative methods of protection against infection that do not directly target viral proteins. Here, we generated heavy-chain-only antibody (VHHs) from an alpaca immunized with the human angiotensin-converting enzyme 2 (hACE2), the major entry receptor for SARS-CoV-2. The VHHs bind hACE2 without affecting its enzymatic activity, and two of them (B07 and B09) inhibit all SARS-CoV-2 isolates tested (Delta, BA.1, BQ1.1, XBB.1.5, XBB.1.16.1, EG.5.1.3, BA.2.86.1). Their X-ray structure in complex with hACE2 show that their epitope overlaps with the footprint of the receptor binding domain (RBD) of the SARS-CoV-2 spike on hACE2. A dimeric B07-Fc fusion construct avidly binds hACE2 with an apparent dissociation constant of 0.1 nM and inhibits in vitro infection of previously tested variants and, of JN.1.1 and KP.3.3 variants, with an IC50 ~ 1 nM. In vivo experiments using K18-hACE2 mice show that intranasal prophylactic administration of B07-Fc confer a dose-dependent protection against SARS-CoV-2 D614G and Omicron variants. These VHHs targeting hACE2 represent potential broad-spectrum therapeutic candidates against potential new emerging coronaviruses using hACE2 as a receptor.

PubMed: 41271706
DOI: 10.1038/s41467-025-65144-w

Experimental method

X-RAY DIFFRACTION (2.69 Å)