8HQT

The complex structure of COPI cargo sorting module with SARS-CoV-2 Spike KxHxx sorting motif

Summary for 8HQT

• Entry DOI: 10.2210/pdb8hqt/pdb
• Descriptor: Coatomer subunit beta', SARS-CoV-2 Spike KxHxx motif (3 entities in total)
• Functional Keywords: sars-cov-2, spike, copi vesicle, kxhxx motif, retention signal, transport protein
• Biological source: Saccharomyces cerevisiae (strain YJM789) (Baker's yeast); More
• Total number of polymer chains: 2
• Total formula weight: 35055.56

Authors

Ma, W.F.,Nan, Y.N.,Yang, M.R.,Li, Y.Q. (deposition date: 2022-12-14, release date: 2023-12-20, Last modification date: 2025-01-29)

Primary citation

Li, Y.,Yang, M.,Nan, Y.,Wang, J.,Wang, S.,Cui, D.,Guo, J.,He, P.,Dai, W.,Zhou, S.,Zhang, Y.,Ma, W.
SARS-CoV-2 spike host cell surface exposure promoted by a COPI sorting inhibitor.
Acta Pharm Sin B, 13:3043-3053, 2023

PubMed Abstract: an insufficient coat protein complex I (COPI) retrieval signal, the majority of SARS-CoV-2 spike (S) is resident in host early secretory organelles and a tiny amount is leaked out in cell surface. Only surface-exposed S can be recognized by B cell receptor (BCR) or anti-S therapeutic monoclonal antibodies (mAbs) that is the trigger step for B cell activation after S mRNA vaccination or infected cell clearance by S mAbs. Now, a drug strategy to promote S host surface exposure is absent. Here, we first combined structural and biochemical analysis to characterize S COPI sorting signals. A potent S COPI sorting inhibitor was then invented, evidently capable of promoting S surface exposure and facilitating infected cell clearance by S antibody-dependent cellular cytotoxicity (ADCC). Importantly, with the inhibitor as a probe, we revealed Omicron BA.1 S is less cell surface exposed than prototypes because of a constellation of S folding mutations, possibly corresponding to its ER chaperone association. Our findings not only suggest COPI is a druggable target against COVID-19, but also highlight SARS-CoV-2 evolution mechanism driven by S folding and trafficking mutations.

PubMed: 37360012
DOI: 10.1016/j.apsb.2023.04.007

Experimental method

X-RAY DIFFRACTION (1.8 Å)