Coronaviruses have glycoprotein “spikes” on their surface, which help the virus to enter host cells by fusing the virus and the cell membrane. The structure of the spike protein of the coronavirus SARS-CoV-2 that causes the current outbreak of COVID-19 has recently been determined by cryogenic electron microscopy (cryo-EM). Cryo-EM uses very low temperatures to allow the determination of biomolecular structures at almost atomic resolution.

The coronavirus spike contains a receptor-binding domain (RBD) subunit, which binds to a receptor on the surface of the host cells’ membrane—the angiotensin-converting enzyme 2 (ACE2). However, the full-length structure of ACE2 has been difficult to determine so far.

Qiang Zhou, Key Westlake Institute for Advanced Study and Westlake University, both, Hangzhou, China, have obtained cryo-EM structures of full-length human ACE2. The measurements were performed in the presence of the neutral amino acid transporter B⁰AT1, which provides stabilization. The structures were recorded both with and without the RBD of the spike protein of SARS-CoV-2. The team co-expressed the ACE2 and B⁰AT1 proteins in a human cell line, mixed a part of the samples with RBD, and studied the resulting complexes using cryo-EM. The structures have an overall resolution of 2.9 Å and a local resolution of 3.5 Å at the ACE2–RBD interface.

The researchers found that the ACE2–B⁰AT1 complex has a dimeric structure, with the ACE2 dimer sandwiched by B⁰AT1. Overall, ACE2 consists of a peptidase domain (PD) on the outer side of the cell membrane and a collectrin-like domain (CLD) that ends with a single transmembrane helix and an intracellular segment. The structure of the ternary RBD–ACE2–B⁰AT1 complex shows that each PD binds to one RBD, mainly via polar interactions. This is similar to the interaction between the SARS virus and ACE2. According to the team, these results could be helpful for the structure-based design of compounds that bind to either ACE2 or the spike protein of coronaviruses and, thus, suppress viral infection.

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• Structural basis for the recognition of the SARS-CoV-2 by full-length human ACE2,
  Renhong Yan, Yuanyuan Zhang, Yaning Li, Lu Xia, Yingying Guo, Qiang Zhou,
  Science 2020.
  https://doi.org/10.1126/science.abb2762

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