A virus-binding hot spot on human angiotensin-converting enzyme 2 is critical for binding of two different coronaviruses

Kailang Wu, Lang Chen, Guiqing Peng, Wenbo Zhou, Christopher A. Pennell, Louis M. Mansky, Robert J. Geraghty, Fang Li

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

How viruses evolve to select their receptor proteins for host cell entry is puzzling. We recently determined the crystal structures of NL63 coronavirus (NL63-CoV) and SARS coronavirus (SARS-CoV) receptor-binding domains (RBDs), each complexed with their common receptor, human angiotensin-converting enzyme 2 (hACE2), and proposed the existence of a virus-binding hot spot on hACE2. Here we investigated the function of this hypothetical hot spot using structure-guided biochemical and functional assays. The hot spot consists of a salt bridge surrounded by hydrophobic tunnel walls. Mutations that disturb the hot spot structure have significant effects on virus/receptor interactions, revealing critical energy contributions from the hot spot structure. The tunnel structure at the NL63-CoV/hACE2 interface is more compact than that at the SARSCoV/hACE2 interface, and hence RBD/hACE2 binding affinities are decreased either by NL63-CoV mutations decreasing the tunnel space or by SARS-CoV mutations increasing the tunnel space. Furthermore, NL63-CoV RBD inhibits hACE2-dependent transduction by SARS-CoV spike protein, a successful application of the hot spot theory that has the potential to become a new antiviral strategy against SARS-CoV infections. These results suggest that the structural features of the hot spot on hACE2 were among the driving forces for the convergent evolution of NL63-CoV and SARS-CoV.

Original languageEnglish (US)
Pages (from-to)5331-5337
Number of pages7
JournalJournal of virology
Volume85
Issue number11
DOIs
StatePublished - Jun 2011

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