SARS-CoV-2 enzyme RdRp: Difference between revisions
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< | <StructureSection load='6yyt' size='340' side='right' caption='Structure of replicating SARS-CoV-2 polymerase (PDB: 6yyt).' scene='84/842066/Sars-cov-2_enzyme_rdrp/1'> | ||
'''RNA-dependent RNA polymerase/ RNA-directed RNA polymerase (RdRp)/ nsp12''' | '''RNA-dependent RNA polymerase/ RNA-directed RNA polymerase (RdRp)/ nsp12''' | ||
== Function == | == Function == | ||
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Responsible for replication and transcription of the viral RNA genome.<ref>[https://zhanglab.ccmb.med.umich.edu/COVID-19/ Modeling of the SARS-COV-2 Genome]</ref><ref>pmid 32200634</ref> | Responsible for replication and transcription of the viral RNA genome.<ref>[https://zhanglab.ccmb.med.umich.edu/COVID-19/ Modeling of the SARS-COV-2 Genome]</ref><ref>pmid 32200634</ref> | ||
Together with the proteins nsp7 and | Together with the proteins nsp7 and a dimer of nsp8, nsp12 forms the <scene name='84/842066/Labelled_subunits/1'>minimal core polymerase complex</scene>. Without its co-factors, nsp12 has a low efficiency in polymerase activity. This complex mediates the RNA synthesis of the virus and is therefore an important part in the replication procedure<ref name="Peng"> PMID:32531208 </ref>. | ||
== Disease == | == Disease == | ||
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== Structure == | == Structure == | ||
Nsp12 consists of three domains, the nidoviruses specific N-terminal nidovirus RdRp-associated nucleotidyltransferase (NiRAN) domain (D60-R249), the C-terminal RdRp domain (S367-F920) as well as an interface domain (A250-R365) connecting both<ref name="Gao"> PMID:32277040 </ref>. At the N-terminus a beta-hairpin motif binds at the interface between the palm subdomain and the NiRAN domain<ref name="Peng"/>. | Nsp12 consists of three domains, the nidoviruses specific N-terminal nidovirus RdRp-associated nucleotidyltransferase <scene name='84/842066/Niran_domain/1'>(NiRAN) domain</scene> (D60-R249), the C-terminal <scene name='84/842066/Rdrp_domain/1'>RdRp domain</scene> (S367-F920) as well as an <scene name='84/842066/Linker_domain/2'>interface domain</scene> (A250-R365) connecting both<ref name="Gao"> PMID:32277040 </ref>. At the N-terminus a beta-hairpin motif binds at the interface between the palm subdomain and the NiRAN domain<ref name="Peng"/>. | ||
The catalytic domain is a right hand | The catalytic domain is a RdRp domain, and is described as a <scene name='84/842066/Hand_model/1'>right hand</scene>, consisting of three subdomains: the finger, palm and thumb. Together with the thumb, the long extended finger forms a closed-ring structure. It contains the motifs A-F that are highly conserved among viral RdRps and motif G <ref name="Peng"/>. Motifs A-E compose the active site at the palm subdomain, with motif C binding to the 3’ end of the RNA template. The motifs F and G are located in the fingers and are responsible for the positioning of the RNA template, while the first turn of the RNA is bound between the fingers and the thumb<ref name="Hillen"> PMID:32438371 </ref>. The fingertip consists of the motif F, interacting with the thumb subdomain and the finger extension loop. The finger extension loops, which themselves are supported by interactions with the nsp7-nsp8.1 heterodimer, stabilize the fingertip loop<ref name="Peng"/>. | ||
The main part of the interaction of the nsp7-nsp8 complex with nsp12 has the nsp7 above the thumb subdomain, while it stabilizes the conformation of the finger extension loops. The second nsp8 (nsp8.2) binds to the top of the finger subdomain and the interface domain and forms a significantly different conformation than nsp8.1<ref name="Peng"/>. | The main part of the interaction of the nsp7-nsp8 complex with nsp12 has the nsp7 above the thumb subdomain, while it stabilizes the conformation of the finger extension loops. The second nsp8 (nsp8.2) binds to the top of the finger subdomain and the interface domain and forms a significantly different conformation than nsp8.1<ref name="Peng"/>. | ||
For entering the catalytic chamber, the RNA gets guided through the template entrance, stabilized by the fingertip and finger extension loops. At the back side of the palm subdomain is a channel for the nucleotide triphosphate to enter the active site. The RNA duplex, made from template and product, can exit at the front of the polymerase, and has later to be separated in further steps by other nsps in order to function<ref name="Peng"/>. | For entering the catalytic chamber, the RNA gets guided through the template entrance, stabilized by the fingertip and finger extension loops. At the back side of the palm subdomain is a channel for the nucleotide triphosphate to enter the active site. The RNA duplex, made from template and product, can exit at the front of the polymerase, and has later to be separated in further steps by other nsps in order to function<ref name="Peng"/>. | ||