Structure of the RNA-dependent RNA polymerase from COVID-19 virus

Abstract

A novel coronavirus (COVID-19 virus) outbreak has caused a global pandemic resulting in tens of thousands of infections and thousands of deaths worldwide. The RNA-dependent RNA polymerase (RdRp, also named nsp12) is the central component of coronaviral replication/transcription machinery and appears to be a primary target for the antiviral drug, remdesivir. We report the cryo-EM structure of COVID-19 virus fulllength nsp12 in complex with cofactors nsp7 and nsp8 at 2.9-Å resolution. In addition to the conserved architecture of the polymerase core of the viral polymerase family, nsp12 possesses a newly identified βhairpin domain at its N terminus. A comparative analysis model shows how remdesivir binds to this polymerase. The structure provides a basis for the design of new antiviral therapeutics targeting viral RdRp.

Structure of replicating SARS-CoV-2 polymerase

“…The RdRp of SARS-CoV-2 is composed of a catalytic subunit called non-structural protein (nsp) 12 14 , and two accessory subunits, nsp8 and nsp7 5,15 . The structure of the RdRp was recently reported 16 and is highly similar to the RdRp of SARS-CoV 17 , a zoonotic coronavirus that spread into the human population in 2002 1 . The nsp12 subunit contains an N-terminal nidovirus RdRp-associated nucleotidyltransferase (NiRAN) domain, an interface domain, and a C-terminal RdRp domain 16,17 .…”

“…The structure of the RdRp was recently reported 16 and is highly similar to the RdRp of SARS-CoV 17 , a zoonotic coronavirus that spread into the human population in 2002 1 . The nsp12 subunit contains an N-terminal nidovirus RdRp-associated nucleotidyltransferase (NiRAN) domain, an interface domain, and a C-terminal RdRp domain 16,17 . The RdRp domain resembles a right hand and comprises the fingers, palm, and thumb subdomains 16,17 that are found in all single-subunit polymerases.…”

“…2). The structure resembles that of the free enzyme 16 , but also reveals large additional protein regions in nsp8 that became ordered upon RNA binding and interact with RNA far outside the core enzyme (Extended Data Figure 3a). These observations are unique, as RdRp complexes of hepatitis C virus 20 , poliovirus 21 , and norovirus 22 contain only one turn of RNA that is however oriented in a similar way (Extended Data Figure 3b).…”

“…The nsp12 subunit contains an N-terminal nidovirus RdRp-associated nucleotidyltransferase (NiRAN) domain, an interface domain, and a C-terminal RdRp domain 16,17 . The RdRp domain resembles a right hand and comprises the fingers, palm, and thumb subdomains 16,17 that are found in all single-subunit polymerases. Subunit nsp7 binds to the thumb, whereas two copies of nsp8 bind to the fingers and thumb subdomains 16,17 .…”

“…The RdRp domain resembles a right hand and comprises the fingers, palm, and thumb subdomains 16,17 that are found in all single-subunit polymerases. Subunit nsp7 binds to the thumb, whereas two copies of nsp8 bind to the fingers and thumb subdomains 16,17 . Structural information is also available for isolated nsp8-nsp7 complexes 18,19 .…”