Sandbox Reserved 1683: Difference between revisions

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== Function of RNA Dependent RNA Polymerases ==

RDRPs allow viruses to replicate their genome as well as carry out transcription. RDRPs catalyze RNA-template-dependent formation of phosphodiester bonds between ribonucleotides, initiating synthesis at the 3' end of the template through a primer-dependent or independent manner proceeding in the 5' to 3' direction.<ref name="Venkataraman>PMID:29439438</ref> RDRPs lack proofreading exonuclease activity which allows for increased rates of mutation that can be selected under pressures from the host's defense mechanisms or other environmental factors.<ref name="Venkataraman /> RDRPs are a good target for antiviral drugs, as viruses depend on them to transcribe and replicate their genome so that they can infect hosts and spread. A 2020 study on the anti-Flu capabilities of 1,2,4-triazolo[1,5-a]pyrimidine-2-carboxamid-based compounds found that such compounds were able to interfere with the PA-PB1 interactions.<ref>PMID:33328103</ref> PA and PB1 are two of the subunits which make up the heterotrimeric Influenza A RDRP that are required for the RDRP to function properly and so the compounds showed promise; however, the study called for more research into such compounds to design drugs with even better anti-Flu properties.<ref>PMID:33328103</ref>

RDRPs allow viruses to replicate their genome as well as carry out transcription. RDRPs catalyze RNA-template-dependent formation of phosphodiester bonds between ribonucleotides, initiating synthesis at the 3' end of the template through a primer-dependent or independent manner proceeding in the 5' to 3' direction.<ref name="Venkataraman>PMID:29439438</ref> RDRPs lack proofreading exonuclease activity which allows for increased rates of mutation that can be selected under pressures from the host's defense mechanisms or other environmental factors.<ref name="Venkataraman" /> RDRPs are a good target for antiviral drugs, as viruses depend on them to transcribe and replicate their genome so that they can infect hosts and spread. A 2020 study on the anti-Flu capabilities of 1,2,4-triazolo[1,5-a]pyrimidine-2-carboxamid-based compounds found that such compounds were able to interfere with the PA-PB1 interactions.<ref>PMID:33328103</ref> PA and PB1 are two of the subunits which make up the heterotrimeric Influenza A RDRP that are required for the RDRP to function properly and so the compounds showed promise; however, the study called for more research into such compounds to design drugs with even better anti-Flu properties.<ref>PMID:33328103</ref>

==Influenza A Basic Structure==

Influenza A itself is made of three subunits: <scene name='89/891373/Pa_subunit_breakdown/1'>PA</scene>, <scene name='89/891373/Pb1_subdomain/3'>PB1</scene>, and <scene name='89/891373/Pb2_subunit_breakdown/1'>PB2</scene>. The PA subunit contains the endonuclease which is responsible for cleaving the transcript that had been pirated from the host 10-12 nucleotides downstream of its 5' cap.<ref>PMID:28115197</ref> The PB1 subunit showcases the characteristic fingers, palm, and thumb domain of other RDRPs in addition to the central active site where the RNA synthesis occurs.<ref>PMID:28115197</ref> The PB2 subunit is likely involved in separating the two strands of the template product within the active site and directs them into their respective exit tunnels.<ref>PMID:28115197</ref>

== Structural Features<ref name="Venkataraman /> ==

== Structural Features<ref name="Venkataraman" /> ==

The major structure of RDRPs is formed by the fingers, palm, and thumb subdomains, with an average length of the core domain being less than 500 amino acids. The three subdomains are involved in template binding, polymerization, and nucleoside triphosphate entry. The palm domain is structurally the most conserved for catalysis, and it serves as the junction of the fingers and thumb domains. The thumb subdomain contains residues involved in packing against the template RNA and stabilizing the initiating NTPs on the template. The fingers subdomain has the role of setting the geometry of the active site serving to hold the template RNA in place and facilitating polymerization. The channels within RDRPs are lined with positively charged residues which promote the binding of the template RNA, the primer, and the NTPs for catalysis. RDRPs also have a set of seven structural motifs labeled A to G, which characterize the conserved structural components of the RDRPs. Motif A houses the catalytic motive DX¬¬2-4D with the first aspartate conserved across various RDRPs. Motif B assists in binding the template RNA and acts as a flexible hinge to accommodate the conformational changes that must take place for template and substrate binding, and it has a conserved glycine residue at the junction of the loop and helix. Motif C contains the conserved GDD motif which is essential for binding metal ions which are required for catalysis within the active site. Motif D also has a conserved glycine which allows it to act as a pivot for conformational changes that are associated with the correct NTP binding. Motif E serves as the primer grip which aids in positioning the 3’ hydroxyl group of the primer for catalysis. Motif F is comprised of conserved positively charged residues which shield the negative charges of the incoming NTP phosphate groups. Motif G consists of a helix that interacts with the priming NTPs, and in Influenza A it is a component of the polymerase acidic (PA) subunit.

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@@ Line 9: / Line 9: @@
 == Function of RNA Dependent RNA Polymerases ==
-RDRPs allow viruses to replicate their genome as well as carry out transcription. RDRPs catalyze RNA-template-dependent formation of phosphodiester bonds between ribonucleotides, initiating synthesis at the 3' end of the template through a primer-dependent or independent manner proceeding in the 5' to 3' direction.<ref name="Venkataraman>PMID:29439438</ref> RDRPs lack proofreading exonuclease activity which allows for increased rates of mutation that can be selected under pressures from the host's defense mechanisms or other environmental factors.<ref name="Venkataraman /> RDRPs are a good target for antiviral drugs, as viruses depend on them to transcribe and replicate their genome so that they can infect hosts and spread. A 2020 study on the anti-Flu capabilities of 1,2,4-triazolo[1,5-a]pyrimidine-2-carboxamid-based compounds found that such compounds were able to interfere with the PA-PB1 interactions.<ref>PMID:33328103</ref> PA and PB1 are two of the subunits which make up the heterotrimeric Influenza A RDRP that are required for the RDRP to function properly and so the compounds showed promise; however, the study called for more research into such compounds to design drugs with even better anti-Flu properties.<ref>PMID:33328103</ref>
+RDRPs allow viruses to replicate their genome as well as carry out transcription. RDRPs catalyze RNA-template-dependent formation of phosphodiester bonds between ribonucleotides, initiating synthesis at the 3' end of the template through a primer-dependent or independent manner proceeding in the 5' to 3' direction.<ref name="Venkataraman>PMID:29439438</ref> RDRPs lack proofreading exonuclease activity which allows for increased rates of mutation that can be selected under pressures from the host's defense mechanisms or other environmental factors.<ref name="Venkataraman" /> RDRPs are a good target for antiviral drugs, as viruses depend on them to transcribe and replicate their genome so that they can infect hosts and spread. A 2020 study on the anti-Flu capabilities of 1,2,4-triazolo[1,5-a]pyrimidine-2-carboxamid-based compounds found that such compounds were able to interfere with the PA-PB1 interactions.<ref>PMID:33328103</ref> PA and PB1 are two of the subunits which make up the heterotrimeric Influenza A RDRP that are required for the RDRP to function properly and so the compounds showed promise; however, the study called for more research into such compounds to design drugs with even better anti-Flu properties.<ref>PMID:33328103</ref>
 ==Influenza A Basic Structure==
 Influenza A itself is made of three subunits: <scene name='89/891373/Pa_subunit_breakdown/1'>PA</scene>, <scene name='89/891373/Pb1_subdomain/3'>PB1</scene>, and <scene name='89/891373/Pb2_subunit_breakdown/1'>PB2</scene>. The PA subunit contains the endonuclease which is responsible for cleaving the transcript that had been pirated from the host 10-12 nucleotides downstream of its 5' cap.<ref>PMID:28115197</ref> The PB1 subunit showcases the characteristic fingers, palm, and thumb domain of other RDRPs in addition to the central active site where the RNA synthesis occurs.<ref>PMID:28115197</ref> The PB2 subunit is likely involved in separating the two strands of the template product within the active site and directs them into their respective exit tunnels.<ref>PMID:28115197</ref>
-== Structural Features<ref name="Venkataraman /> ==
+== Structural Features<ref name="Venkataraman" /> ==
 The major structure of RDRPs is formed by the fingers, palm, and thumb subdomains, with an average length of the core domain being less than 500 amino acids. The three subdomains are involved in template binding, polymerization, and nucleoside triphosphate entry. The palm domain is structurally the most conserved for catalysis, and it serves as the junction of the fingers and thumb domains. The thumb subdomain contains residues involved in packing against the template RNA and stabilizing the initiating NTPs on the template. The fingers subdomain has the role of setting the geometry of the active site serving to hold the template RNA in place and facilitating polymerization. The channels within RDRPs are lined with positively charged residues which promote the binding of the template RNA, the primer, and the NTPs for catalysis. RDRPs also have a set of seven structural motifs labeled A to G, which characterize the conserved structural components of the RDRPs. Motif A houses the catalytic motive DX¬¬2-4D with the first aspartate conserved across various RDRPs. Motif B assists in binding the template RNA and acts as a flexible hinge to accommodate the conformational changes that must take place for template and substrate binding, and it has a conserved glycine residue at the junction of the loop and helix. Motif C contains the conserved GDD motif which is essential for binding metal ions which are required for catalysis within the active site. Motif D also has a conserved glycine which allows it to act as a pivot for conformational changes that are associated with the correct NTP binding. Motif E serves as the primer grip which aids in positioning the 3’ hydroxyl group of the primer for catalysis. Motif F is comprised of conserved positively charged residues which shield the negative charges of the incoming NTP phosphate groups. Motif G consists of a helix that interacts with the priming NTPs, and in Influenza A it is a component of the polymerase acidic (PA) subunit.