Structural basis for bat receptor recognition by SARS-CoV-2 and bat SARS2-like coronaviruses

Coronaviruses evolve to optimize receptor recognition in their natural hosts. A key mystery of COVID-19 is why the SARS-CoV-2 receptor-binding domain (RBD) binds human ACE2 with such high affinity despite limited time for adaptation, while some bat-derived RBDs paradoxically bind human ACE2 more strongly than bat ACE2. To investigate, we compared the RBDs of SARS-CoV-2 and BANAL-52, a related bat coronavirus, examining their interactions with ACE2 from Rhinolophus sinicus (RsBat) and from human. Structural and biochemical analyses revealed that BANAL-52 RBD is well adapted for binding to RsBat ACE2, with His498 of BANAL-52 RBD pairing favorably with His41 of RsBat ACE2. By contrast, SARS-CoV-2 RBD favors human ACE2, largely due to His34 and Met82 in human ACE2, residues that generally enhance RBD binding. These results show that receptor recognition by SARS-CoV-2 and related bat coronaviruses is consistent with established structural principles and provide structural insights relevant to the evolutionary origins of COVID-19. Structural and biochemical analyses resolve longstanding paradoxes in how SARS-CoV-2 and related bat viruses use their receptor-binding domains to recognize ACE2 receptors from human and bats, providing insights into the origins of COVID-19