Institute of Biological Chemistry, Academia Sinica
The Alpha variant of SARS-CoV-2, also known as the B.1.1.7 strain, was first identified in the UK in late 2020. It soon spread across the world before being overtaken by the Delta variant that emerged in India. These variants of concern (VOCs) are essentially defined by the mutations on the spike protein. Changes in the spike protein sequence can alter its structure to enhance its ability to bind to host cell receptor molecules and/or evade host immunity that collectively cause the increase of transmissibility. To understand how the mutations affect the molecular structure and function of the spike protein of the Alpha variant, a research team led by Dr Shang-Te Danny Hsu at the Institute of Biological Chemistry, Academia Sinica, used state-of-the-art cryo-electron microscopy (cryo-EM) to determine the atomic structure of the spike protein of the Alpha variant. As a result, they are able to visualize the atomic details of how the mutations on the spike protein alter the molecular structure to enhance the affinity towards host receptor molecular, angiotensin-converting enzyme 2 (ACE2), and how the other mutations help SARS-CoV-2 evade potent neutralizing antibodies that target the receptor-binding domain (RBD).
Their findings, published in Nature Structural & Molecular Biology, demonstrate that the Alpha variant evolves a unique A570D mutation that serves as a molecular switch to control the opening and closing of the RBD that is essential for host recognition. They call this a pedal-bin-like mechanism. Additionally, the atomic structure of the Alpha variant’s spike protein in complex with the host receptor ACE2 shows that another point mutation N501Y makes a new favorable contact with ACE2 that leads to enhanced binding affinity, which could help increase the infectivity. The N501Y also alters the molecular structure recognized by antibodies (known as the epitope), and renders some therapeutic antibodies less effective. Notably, the N501Y mutation is also present in the Beta (South African, B.1.351) variant and Gamma (Brazilian, P.1) variant, suggesting a common cause of increased transmissibility, although these variants originated from different places.
To overcome this issue, the research team demonstrates that two monoclonal antibodies developed by Dr. Han-Chung Wu, Director of the Biomedical Translation Research Center (BioTReC), Academia Sinica, can efficiently inhibit ACE2 binding by different spike variants, including that of the Alpha variant. The cryo-EM structure of the spike protein in complex with the two antibodies underscores the potential of their combined use as an antibody cocktail to mitigate COVID-19 caused by different SARS-CoV-2 variants.
