4m5o

<StructureSection load='4m5o' size='340' side='right' caption='[[4m5o]], [[Resolution|resolution]] 2.00&Aring;' scene=''>

<table><tr><td colspan='2'>[[4m5o]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Influenza_a_virus_(a/lima/wrair1695p/2009(h1n1)) Influenza a virus (a/lima/wrair1695p/2009(h1n1))]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4M5O OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4M5O FirstGlance]. <br>

</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=X48:3-HYDROXY-6-PHENYLPYRIDIN-2(5H)-ONE'>X48</scene></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=985958 Influenza A virus (A/Lima/WRAIR1695P/2009(H1N1))])</td></tr>

<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4m5o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4m5o OCA], [http://pdbe.org/4m5o PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4m5o RCSB], [http://www.ebi.ac.uk/pdbsum/4m5o PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4m5o ProSAT]</span></td></tr>

== Function ==

[[http://www.uniprot.org/uniprot/F0TRT1_9INFA F0TRT1_9INFA]] Implicated in endonuclease cleavage of capped RNA primers. Displays an elongation factor activity in viral RNA synthesis. Dispensable for viral transcription, but not replication (By similarity).[SAAS:SAAS001009_004_020464]

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== Publication Abstract from PubMed ==

Seasonal and pandemic influenza viruses continue to be a leading global health concern. Emerging resistance to the current drugs and the variable efficacy of vaccines underscore the need for developing new flu drugs that will be broadly effective against wild-type and drug-resistant influenza strains. Here, we report the discovery and development of a class of inhibitors targeting the cap-snatching endonuclease activity of the viral polymerase. A high-resolution crystal form of pandemic 2009 H1N1 influenza polymerase acidic protein N-terminal endonuclease domain (PAN) was engineered and used for fragment screening leading to the identification of new chemical scaffolds binding to the PAN active site cleft. During the course of screening, binding of a third metal ion that is potentially relevant to endonuclease activity was detected in the active site cleft of PAN in the presence of a fragment. Using structure-based optimization, we developed a highly potent hydroxypyridinone series of compounds from a fragment hit that defines a new mode of chelation to the active site metal ions. A compound from the series demonstrating promising enzymatic inhibition in a fluorescence-based enzyme assay with an IC50 value of 11 nM was found to have an antiviral activity (EC50) of 11 muM against PR8 H1N1 influenza A in MDCK cells.

Crystallographic Fragment Screening and Structure-Based Optimization Yields a New Class of Influenza Endonuclease Inhibitors.,Bauman JD, Patel D, Baker SF, Vijayan RS, Xiang A, Parhi AK, Martinez-Sobrido L, Lavoie EJ, Das K, Arnold E ACS Chem Biol. 2013 Sep 13. PMID:23978130<ref>PMID:23978130</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>

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<div class="pdbe-citations 4m5o" style="background-color:#fffaf0;"></div>

== References ==

<references/>

[[Category: Arnold, E]]

[[Category: Bauman, J D]]

[[Category: Das, K]]

[[Category: Patel, D]]

[[Category: Rna binding protein-inhibitor complex]]