View source for 4qbb


==Structure of the foot-and-mouth disease virus leader proteinase in complex with inhibitor (N~2~-[(3S)-4-({(2R)-1-[(4-CARBAMIMIDAMIDOBUTYL)AMINO]-4-METHYL-1-OXOPENTAN-2-YL}AMINO)-3-HYDROXY-4-OXOBUTANOYL]-L-ARGINYL-L-PROLINAMIDE)==
<StructureSection load='4qbb' size='340' side='right'caption='[[4qbb]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4qbb]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Foot-and-mouth_disease_virus_(strain_O1) Foot-and-mouth disease virus (strain O1)]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4QBB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4QBB FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.6&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=E69:N~2~-[(3S)-4-({(2R)-1-[(4-CARBAMIMIDAMIDOBUTYL)AMINO]-4-METHYL-1-OXOPENTAN-2-YL}AMINO)-3-HYDROXY-4-OXOBUTANOYL]-L-ARGINYL-L-PROLINAMIDE'>E69</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4qbb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qbb OCA], [https://pdbe.org/4qbb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4qbb RCSB], [https://www.ebi.ac.uk/pdbsum/4qbb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4qbb ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/POLG_FMDVO POLG_FMDVO] The leader protease autocatalytically cleaves itself from the polyprotein at the L/VP0 junction. It also cleaves the host translation initiation factor EIF4G1 and EIF4G3, in order to shut down the capped cellular mRNA transcription.<ref>PMID:8386879</ref> <ref>PMID:11034318</ref> <ref>PMID:15016848</ref> <ref>PMID:18614639</ref>   Capsid proteins VP1, VP2, VP3 and VP4 form a closed capsid enclosing the viral positive strand RNA genome. VP4 lies on the inner surface of the protein shell formed by VP1, VP2 and VP3. All the three latter proteins contain a beta-sheet structure called beta-barrel jelly roll. Together they form an icosahedral capsid (T=3) composed of 60 copies of each VP1, VP2, and VP3, with a diameter of approximately 300 Angstroms. VP1 is situated at the 12 fivefold axes, whereas VP2 and VP3 are located at the quasi-sixfold axes. The capsid interacts with host heparan sulfate and various integrins (alphavbeta6, alphavbeta1, alphavbeta3, alpha5beta1, alphavbeta8) to provide virion attachment to target Attachment via host integrins induces virion internalization predominantly through clathrin-mediated endocytosis. In strains adapted to cell culture, attachment to heparan sulfate can also be used and induces virion internalization through clathrin- and caveolin-independent endocytosis.<ref>PMID:8386879</ref> <ref>PMID:11034318</ref> <ref>PMID:15016848</ref> <ref>PMID:18614639</ref>   Protein VP0: VP0 precursor is a component of immature procapsids (By similarity).<ref>PMID:8386879</ref> <ref>PMID:11034318</ref> <ref>PMID:15016848</ref> <ref>PMID:18614639</ref>   Protein 2B: Affects membrane integrity and cause an increase in membrane permeability (By similarity).<ref>PMID:8386879</ref> <ref>PMID:11034318</ref> <ref>PMID:15016848</ref> <ref>PMID:18614639</ref>   Protein 2C: Associates with and induces structural rearrangements of intracellular membranes. It displays RNA-binding, nucleotide binding and NTPase activities (By similarity).<ref>PMID:8386879</ref> <ref>PMID:11034318</ref> <ref>PMID:15016848</ref> <ref>PMID:18614639</ref>   Protein 3A, via its hydrophobic domain, serves as membrane anchor (By similarity).<ref>PMID:8386879</ref> <ref>PMID:11034318</ref> <ref>PMID:15016848</ref> <ref>PMID:18614639</ref>   Protein 3B-1, 3B-2 and 3B-3 are covalently linked to the 5'-end of both the positive-strand and negative-strand genomic RNAs. They acts as a genome-linked replication primer (By similarity).<ref>PMID:8386879</ref> <ref>PMID:11034318</ref> <ref>PMID:15016848</ref> <ref>PMID:18614639</ref>   Protease 3C: cysteine protease that generates mature viral proteins from the precursor polyprotein. In addition to its proteolytic activity, it binds to viral RNA, and thus influences viral genome replication. RNA and substrate bind cooperatively to the protease (By similarity).<ref>PMID:8386879</ref> <ref>PMID:11034318</ref> <ref>PMID:15016848</ref> <ref>PMID:18614639</ref>   RNA-directed RNA polymerase 3D-POL replicates genomic and antigenomic RNA by recognizing replications specific signals (By similarity).<ref>PMID:8386879</ref> <ref>PMID:11034318</ref> <ref>PMID:15016848</ref> <ref>PMID:18614639</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Translation of foot-and-mouth disease virus RNA initiates at one of two start codons leading to the synthesis of two forms of leader proteinase Lpro (Labpro and Lbpro). These forms free themselves from the viral polyprotein by intra- and intermolecular self-processing and subsequently cleave the cellular eukaryotic initiation factor (eIF) 4G. During infection, Lbpro removes six residues from its own C-terminus, generating sLbpro. We present the structure of sLbpro bound to the inhibitor E64-R-P-NH2, illustrating how sLbpro can cleave between Lys/Gly and Gly/Arg pairs. In intermolecular cleavage on polyprotein substrates, Lbpro was unaffected by P1 or P1' substitutions and processed a substrate containing nine eIF4GI cleavage site residues whereas sLbpro failed to cleave the eIF4GI containing substrate and cleaved appreciably more slowly on mutated substrates. Introduction of 70 eIF4GI residues bearing the Lbpro binding site restored cleavage. These data imply that Lbpro and sLbpro may have different functions in infected cells.

Foot-and-mouth disease virus leader proteinase: Structural insights into the mechanism of intermolecular cleavage.,Steinberger J, Grishkovskaya I, Cencic R, Juliano L, Juliano MA, Skern T Virology. 2014 Sep 18;468-470C:397-408. doi: 10.1016/j.virol.2014.08.023. PMID:25240326<ref>PMID:25240326</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 4qbb" style="background-color:#fffaf0;"></div>

==See Also==
*[[Virus protease 3D structures|Virus protease 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Cencic R]]
[[Category: Grishkovskaya I]]
[[Category: Juliano L]]
[[Category: Juliano MA]]
[[Category: Skern T]]
[[Category: Steinberger J]]