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4zro

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Revision as of 16:13, 15 November 2017

2.1 A X-Ray Structure of FIPV-3CLpro bound to covalent inhibitor

Structural highlights

4zro is a 8 chain structure with sequence from Fcov. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
NonStd Res:	,
Gene:	rep, 1a-1b (FCoV)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[R1AB_FIPV] The replicase polyprotein of coronaviruses is a multifunctional protein: it contains the activities necessary for the transcription of negative stranded RNA, leader RNA, subgenomic mRNAs and progeny virion RNA as well as proteinases responsible for the cleavage of the polyprotein into functional products. The papain-like proteinase 1 (PLP1) and papain-like proteinase 2 (PLP2) are responsible for the cleavages located at the N-terminus of the replicase polyprotein. In addition, PLP2 possesses a deubiquitinating/deISGylating activity and processes both 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains from cellular substrates. PLP2 also antagonizes innate immune induction of type I interferon by blocking the nuclear translocation of host IRF-3 (By similarity). The main proteinase 3CL-PRO is responsible for the majority of cleavages as it cleaves the C-terminus of replicase polyprotein at 11 sites. Recognizes substrates containing the core sequence [ILMVF]-Q-|-[SGACN]. Inhibited by the substrate-analog Cbz-Val-Asn-Ser-Thr-Leu-Gln-CMK. Also contains an ADP-ribose-1-phosphate (ADRP)-binding function (By similarity). The helicase which contains a zinc finger structure displays RNA and DNA duplex-unwinding activities with 5' to 3' polarity. ATPase activity is strongly stimulated by poly(U), poly(dT), poly(C), poly(dA), but not by poly(G) (By similarity). The exoribonuclease acts on both ssRNA and dsRNA in a 3' to 5' direction (By similarity). Nsp7-nsp8 hexadecamer may possibly confer processivity to the polymerase, maybe by binding to dsRNA or by producing primers utilized by the latter (By similarity). Nsp9 is a ssRNA-binding protein (By similarity). NendoU is a Mn(2+)-dependent, uridylate-specific enzyme, which leaves 2'-3'-cyclic phosphates 5' to the cleaved bond (By similarity).

Publication Abstract from PubMed

Feline infectious peritonitis (FIP) is a deadly disease that effects both domestic and wild cats and is caused by a mutation in feline coronavirus (FCoV) that allows the virus to replicate in macrophages. Currently, there are no treatments or vaccines available for the treatment of FIP even though it kills approximately 5% of cats in multi-cat households per year. In an effort to develop small molecule drugs targeting FIP for the treatment of cats, we screened a small set of designed peptidomimetic inhibitors for inhibition of FIPV-3CL(pro), identifying two compounds with low to sub-micromolar inhibition, compound 6 (IC50=0.59+/-0.06muM) and compound 7 (IC50=1.3+/-0.1muM). We determined the first X-ray crystal structure of FIPV-3CL(pro) in complex with the best inhibitor identified, compound 6, to a resolution of 2.10A to better understand the structural basis for inhibitor specificity. Our study provides important insights into the structural requirements for the inhibition of FIPV-3CL(pro) by peptidomimetic inhibitors and expands the current structural knowledge of coronaviral 3CL(pro) architecture.

X-ray structure and inhibition of the feline infectious peritonitis virus 3C-like protease: Structural implications for drug design.,St John SE, Therkelsen MD, Nyalapatla PR, Osswald HL, Ghosh AK, Mesecar AD Bioorg Med Chem Lett. 2015 Nov 15;25(22):5072-7. doi: 10.1016/j.bmcl.2015.10.023., Epub 2015 Oct 13. PMID:26592814^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ St John SE, Therkelsen MD, Nyalapatla PR, Osswald HL, Ghosh AK, Mesecar AD. X-ray structure and inhibition of the feline infectious peritonitis virus 3C-like protease: Structural implications for drug design. Bioorg Med Chem Lett. 2015 Nov 15;25(22):5072-7. doi: 10.1016/j.bmcl.2015.10.023., Epub 2015 Oct 13. PMID:26592814 doi:http://dx.doi.org/10.1016/j.bmcl.2015.10.023

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4zro"

@@ Line 1: / Line 1: @@
 ==2.1 A X-Ray Structure of FIPV-3CLpro bound to covalent inhibitor==
 <StructureSection load='4zro' size='340' side='right' caption='[[4zro]], [[Resolution|resolution]] 2.06&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4zro]] is a 8 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZRO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ZRO FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4zro]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/Fcov Fcov]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZRO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ZRO FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene></td></tr>
 <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=BOC:TERT-BUTYL+HYDROGEN+CARBONATE'>BOC</scene>, <scene name='pdbligand=CEV:ETHYL+(4R)-4-AMINO-5-[(3S)-2-OXOPYRROLIDIN-3-YL]PENTANOATE'>CEV</scene></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=4zro FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zro OCA], [http://pdbe.org/4zro PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4zro RCSB], [http://www.ebi.ac.uk/pdbsum/4zro PDBsum]</span></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">rep, 1a-1b ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=33734 FCoV])</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=4zro FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zro OCA], [http://pdbe.org/4zro PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4zro RCSB], [http://www.ebi.ac.uk/pdbsum/4zro PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4zro ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 22: / Line 24: @@
 __TOC__
 </StructureSection>
+[[Category: Fcov]]
 [[Category: John, S E.St]]
 [[Category: Mesecar, A D]]
 [[Category: Coronavirus]]
-[[Category: Fcov]]
 [[Category: Feline infectious peritonitis]]
 [[Category: Fipv]]

4zro

From Proteopedia

Revision as of 16:13, 15 November 2017

2.1 A X-Ray Structure of FIPV-3CLpro bound to covalent inhibitor

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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