7KL9

Structure of the SARS-CoV-2 S 6P trimer in complex with the ACE2 protein decoy, CTC-445.2 (State 4)

Summary for 7KL9

• Entry DOI: 10.2210/pdb7kl9/pdb
• EMDB information: 22916
• Descriptor: Spike glycoprotein, CTC-445.2 inhibitor, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total)
• Functional Keywords: sars-cov-2, ace2 decoy, mini-protein, inhibitor, covid-19, antiviral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV); More
• Total number of polymer chains: 6
• Total formula weight: 476488.16

Authors

Barnes, C.O.,Bjorkman, P.J. (deposition date: 2020-10-29, release date: 2020-11-11, Last modification date: 2024-10-30)

Primary citation

Linsky, T.W.,Vergara, R.,Codina, N.,Nelson, J.W.,Walker, M.J.,Su, W.,Barnes, C.O.,Hsiang, T.Y.,Esser-Nobis, K.,Yu, K.,Reneer, Z.B.,Hou, Y.J.,Priya, T.,Mitsumoto, M.,Pong, A.,Lau, U.Y.,Mason, M.L.,Chen, J.,Chen, A.,Berrocal, T.,Peng, H.,Clairmont, N.S.,Castellanos, J.,Lin, Y.R.,Josephson-Day, A.,Baric, R.S.,Fuller, D.H.,Walkey, C.D.,Ross, T.M.,Swanson, R.,Bjorkman, P.J.,Gale Jr., M.,Blancas-Mejia, L.M.,Yen, H.L.,Silva, D.A.
De novo design of potent and resilient hACE2 decoys to neutralize SARS-CoV-2.
Science, 370:1208-1214, 2020

PubMed Abstract: We developed a de novo protein design strategy to swiftly engineer decoys for neutralizing pathogens that exploit extracellular host proteins to infect the cell. Our pipeline allowed the design, validation, and optimization of de novo human angiotensin-converting enzyme 2 (hACE2) decoys to neutralize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The best monovalent decoy, CTC-445.2, bound with low nanomolar affinity and high specificity to the receptor-binding domain (RBD) of the spike protein. Cryo-electron microscopy (cryo-EM) showed that the design is accurate and can simultaneously bind to all three RBDs of a single spike protein. Because the decoy replicates the spike protein target interface in hACE2, it is intrinsically resilient to viral mutational escape. A bivalent decoy, CTC-445.2d, showed ~10-fold improvement in binding. CTC-445.2d potently neutralized SARS-CoV-2 infection of cells in vitro, and a single intranasal prophylactic dose of decoy protected Syrian hamsters from a subsequent lethal SARS-CoV-2 challenge.

PubMed: 33154107
DOI: 10.1126/science.abe0075

Experimental method

ELECTRON MICROSCOPY (4.1 Å)