7RPV

Crystal structure of affinity-enhancing and catalytically inactive ACE2 in complex with SARS-CoV-2 RBD

Summary for 7RPV

• Entry DOI: 10.2210/pdb7rpv/pdb
• Descriptor: Processed angiotensin-converting enzyme 2, Spike protein S1, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: sars-cov-2, receptor binding domain, engineered human ace2, enhanced affinity, catalytic-null, zinc binding site, hydrolase-viral protein complex, hydrolase/viral protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 8
• Total formula weight: 380059.28

Authors

Chen, Y.,Tolbert, D.W.,Pazgier, M. (deposition date: 2021-08-04, release date: 2021-12-15, Last modification date: 2024-10-23)

Primary citation

Chen, Y.,Sun, L.,Ullah, I.,Beaudoin-Bussieres, G.,Anand, S.P.,Hederman, A.P.,Tolbert, W.D.,Sherburn, R.,Nguyen, D.N.,Marchitto, L.,Ding, S.,Wu, D.,Luo, Y.,Gottumukkala, S.,Moran, S.,Kumar, P.,Piszczek, G.,Mothes, W.,Ackerman, M.E.,Finzi, A.,Uchil, P.D.,Gonzalez, F.J.,Pazgier, M.
Engineered ACE2-Fc counters murine lethal SARS-CoV-2 infection through direct neutralization and Fc-effector activities.
Biorxiv, 2021

PubMed Abstract: Soluble Angiotensin-Converting Enzyme 2 (ACE2) constitutes an attractive antiviral capable of targeting a wide range of coronaviruses utilizing ACE2 as their receptor. Here, using structure-guided approaches, we developed divalent ACE2 molecules by grafting the extracellular ACE2-domain onto a human IgG1 or IgG3 (ACE2-Fc). These ACE2-Fcs harbor structurally validated mutations that enhance spike (S) binding and remove angiotensin enzymatic activity. The lead variant bound tightly to S, mediated neutralization of SARS-CoV-2 variants of concern (VOCs) with sub-nanomolar IC and was capable of robust Fc-effector functions, including antibody-dependent-cellular cytotoxicity, phagocytosis and complement deposition. When tested in a stringent K18-hACE2 mouse model, it delayed death or effectively resolved lethal SARS-CoV-2 infection in a prophylactic or therapeutic setting utilizing the combined effect of neutralization and Fc-effector functions. These data confirm the utility of ACE2-Fcs as valuable agents in preventing and eliminating SARS-CoV-2 infection and demonstrate that ACE2-Fc therapeutic activity require Fc-effector functions.

PubMed: 34845451
DOI: 10.1101/2021.11.24.469776

Experimental method

X-RAY DIFFRACTION (3.54 Å)