View source for 6qwl


==Influenza B virus (B/Panama/45) polymerase Hetermotrimer in complex with 3'5' cRNA promoter==
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== Structural highlights ==
<table><tr><td colspan='2'>[[6qwl]] is a 5 chain structure with sequence from [http://en.wikipedia.org/wiki/Inbp9 Inbp9]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6QWL OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6QWL FirstGlance]. <br>
</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=408929 INBP9]), PB1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=408929 INBP9]), PB2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=408929 INBP9])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/RNA-directed_RNA_polymerase RNA-directed RNA polymerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.48 2.7.7.48] </span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6qwl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6qwl OCA], [http://pdbe.org/6qwl PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6qwl RCSB], [http://www.ebi.ac.uk/pdbsum/6qwl PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6qwl ProSAT]</span></td></tr>
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== Function ==
[[http://www.uniprot.org/uniprot/PA_INBP9 PA_INBP9]] Plays an essential role in viral RNA transcription and replication by forming the heterotrimeric polymerase complex together with PB1 and PB2 subunits. The complex transcribes viral mRNAs by using a unique mechanism called cap-snatching. It consists in the hijacking and cleavage of host capped pre-mRNAs. These short capped RNAs are then used as primers for viral mRNAs. The PB2 subunit is responsible for the binding of the 5' cap of cellular pre-mRNAs which are subsequently cleaved after 10-13 nucleotides by the PA subunit that carries the endonuclease activity. [[http://www.uniprot.org/uniprot/PB2_INBP9 PB2_INBP9]] Plays an essential role in transcription initiation and cap-stealing mechanism, in which cellular capped pre-mRNAs are used to generate primers for viral transcription. Recognizes and binds a wide range of cap structures of target pre-RNAs which are subsequently cleaved after 10-13 nucleotides by the viral protein PA. Plays a role in the initiation of the viral genome replication and modulates the activity of the ribonucleoprotein (RNP) complex. [[http://www.uniprot.org/uniprot/RDRP_INBP9 RDRP_INBP9]] RNA-dependent RNA polymerase which is responsible for replication and transcription of virus RNA segments. The transcription of viral mRNAs occurs by a unique mechanism called cap-snatching. 5' methylated caps of cellular mRNAs are cleaved after 10-13 nucleotides by PA. In turn, these short capped RNAs are used as primers by PB1 for transcription of viral mRNAs. During virus replication, PB1 initiates RNA synthesis and copy vRNA into complementary RNA (cRNA) which in turn serves as a template for the production of more vRNAs. 
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== Publication Abstract from PubMed ==
Influenza A viruses are responsible for seasonal epidemics, and pandemics can arise from the transmission of novel zoonotic influenza A viruses to humans(1,2). Influenza A viruses contain a segmented negative-sense RNA genome, which is transcribed and replicated by the viral-RNA-dependent RNA polymerase (FluPolA) composed of PB1, PB2 and PA subunits(3-5). Although the high-resolution crystal structure of FluPolA of bat influenza A virus has previously been reported(6), there are no complete structures available for human and avian FluPolA. Furthermore, the molecular mechanisms of genomic viral RNA (vRNA) replication-which proceeds through a complementary RNA (cRNA) replicative intermediate, and requires oligomerization of the polymerase(7-10)-remain largely unknown. Here, using crystallography and cryo-electron microscopy, we determine the structures of FluPolA from human influenza A/NT/60/1968 (H3N2) and avian influenza A/duck/Fujian/01/2002 (H5N1) viruses at a resolution of 3.0-4.3 A, in the presence or absence of a cRNA or vRNA template. In solution, FluPolA forms dimers of heterotrimers through the C-terminal domain of the PA subunit, the thumb subdomain of PB1 and the N1 subdomain of PB2. The cryo-electron microscopy structure of monomeric FluPolA bound to the cRNA template reveals a binding site for the 3' cRNA at the dimer interface. We use a combination of cell-based and in vitro assays to show that the interface of the FluPolA dimer is required for vRNA synthesis during replication of the viral genome. We also show that a nanobody (a single-domain antibody) that interferes with FluPolA dimerization inhibits the synthesis of vRNA and, consequently, inhibits virus replication in infected cells. Our study provides high-resolution structures of medically relevant FluPolA, as well as insights into the replication mechanisms of the viral RNA genome. In addition, our work identifies sites in FluPolA that could be targeted in the development of antiviral drugs.

Structures of influenza A virus RNA polymerase offer insight into viral genome replication.,Fan H, Walker AP, Carrique L, Keown JR, Serna Martin I, Karia D, Sharps J, Hengrung N, Pardon E, Steyaert J, Grimes JM, Fodor E Nature. 2019 Sep;573(7773):287-290. doi: 10.1038/s41586-019-1530-7. Epub 2019 Sep, 4. PMID:31485076<ref>PMID:31485076</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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==See Also==
*[[RNA polymerase 3D structures|RNA polymerase 3D structures]]
== References ==
<references/>
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</SX>
[[Category: Inbp9]]
[[Category: Large Structures]]
[[Category: RNA-directed RNA polymerase]]
[[Category: Carrique, L]]
[[Category: Fan, H]]
[[Category: Fodor, E]]
[[Category: Grimes, J M]]
[[Category: Keown, J R]]
[[Category: Influenza some]]
[[Category: Influenza dimer]]
[[Category: Influenza polymerase]]
[[Category: Rdrp]]
[[Category: Rna binding protein]]
[[Category: Rna polymerase]]