6jij

From Proteopedia

(Difference between revisions)

Current revision

The Crystal Structure of Main Protease from Mouse Hepatitis Virus A59 in Complex with an inhibitor

Structural highlights

6jij is a 6 chain structure with sequence from Murine hepatitis virus strain A59 and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.65Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

R1AB_CVMA5 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 (PL1-PRO) and papain-like proteinase 2 (PL2-PRO) 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. Antagonizes innate immune induction of type I interferon by blocking the phosphorylation, dimerization and subsequent 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

Mouse hepatitis virus A59 (MHV-A59) is a representative member of the genus betacoronavirus within the subfamily Coronavirinae, which infects the liver, brain and respiratory tract. Through different inoculation routes, MHV-A59 can provide animal models for encephalitis, hepatitis and pneumonia to explore viral life machinery and virus-host interactions. In viral replication, non-structural protein 5 (Nsp5), also termed main protease (M(pro)), plays a dominant role in processing coronavirus-encoded polyproteins and is thus recognized as an ideal target of anti-coronavirus agents. However, no structure of the MHV-A59 M(pro) has been reported, and molecular exploration of the catalysis mechanism remains hindered. Here, we solved the crystal structure of the MHV-A59 M(pro) complexed with a Michael acceptor-based inhibitor, N3. Structural analysis revealed that the Cbeta of the vinyl group of N3 covalently bound to C145 of the catalytic dyad of M(pro), which irreversibly inactivated cysteine protease activity. The lactam ring of the P1 side chain and the isobutyl group of the P2 side chain, which mimic the conserved residues at the same positions of the substrate, fit well into the S1 and S2 pockets. Through a comparative study with M(pro) of other coronaviruses, we observed that the substrate-recognition pocket and enzyme inhibitory mechanism is highly conservative. Altogether, our study provided structural features of MHV-A59 M(pro) and indicated that a Michael acceptor inhibitor is an ideal scaffold for antiviral drugs.

The crystal structure of main protease from mouse hepatitis virus A59 in complex with an inhibitor.,Cui W, Cui S, Chen C, Chen X, Wang Z, Yang H, Zhang L Biochem Biophys Res Commun. 2019 Apr 16;511(4):794-799. doi:, 10.1016/j.bbrc.2019.02.105. Epub 2019 Mar 2. PMID:30833083^[1]

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

References

↑ Cui W, Cui S, Chen C, Chen X, Wang Z, Yang H, Zhang L. The crystal structure of main protease from mouse hepatitis virus A59 in complex with an inhibitor. Biochem Biophys Res Commun. 2019 Apr 16;511(4):794-799. doi:, 10.1016/j.bbrc.2019.02.105. Epub 2019 Mar 2. PMID:30833083 doi:http://dx.doi.org/10.1016/j.bbrc.2019.02.105

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/6jij"

Categories: Large Structures | Murine hepatitis virus strain A59 | Synthetic construct | Cui SS | Cui W

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 6jij is ON HOLD  until Paper Publication
+==The Crystal Structure of Main Protease from Mouse Hepatitis Virus A59 in Complex with an inhibitor==
+<StructureSection load='6jij' size='340' side='right'caption='[[6jij]], [[Resolution|resolution]] 2.65&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[6jij]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Murine_hepatitis_virus_strain_A59 Murine hepatitis virus strain A59] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6JIJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6JIJ 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]] 2.65&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=010:PHENYLMETHANOL'>010</scene>, <scene name='pdbligand=02J:5-METHYL-1,2-OXAZOLE-3-CARBOXYLIC+ACID'>02J</scene>, <scene name='pdbligand=PJE:(E,4S)-4-AZANYL-5-[(3S)-2-OXIDANYLIDENEPYRROLIDIN-3-YL]PENT-2-ENOIC+ACID'>PJE</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=6jij FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6jij OCA], [https://pdbe.org/6jij PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6jij RCSB], [https://www.ebi.ac.uk/pdbsum/6jij PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6jij ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/R1AB_CVMA5 R1AB_CVMA5] 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 (PL1-PRO) and papain-like proteinase 2 (PL2-PRO) 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. Antagonizes innate immune induction of type I interferon by blocking the phosphorylation, dimerization and subsequent 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).
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Mouse hepatitis virus A59 (MHV-A59) is a representative member of the genus betacoronavirus within the subfamily Coronavirinae, which infects the liver, brain and respiratory tract. Through different inoculation routes, MHV-A59 can provide animal models for encephalitis, hepatitis and pneumonia to explore viral life machinery and virus-host interactions. In viral replication, non-structural protein 5 (Nsp5), also termed main protease (M(pro)), plays a dominant role in processing coronavirus-encoded polyproteins and is thus recognized as an ideal target of anti-coronavirus agents. However, no structure of the MHV-A59 M(pro) has been reported, and molecular exploration of the catalysis mechanism remains hindered. Here, we solved the crystal structure of the MHV-A59 M(pro) complexed with a Michael acceptor-based inhibitor, N3. Structural analysis revealed that the Cbeta of the vinyl group of N3 covalently bound to C145 of the catalytic dyad of M(pro), which irreversibly inactivated cysteine protease activity. The lactam ring of the P1 side chain and the isobutyl group of the P2 side chain, which mimic the conserved residues at the same positions of the substrate, fit well into the S1 and S2 pockets. Through a comparative study with M(pro) of other coronaviruses, we observed that the substrate-recognition pocket and enzyme inhibitory mechanism is highly conservative. Altogether, our study provided structural features of MHV-A59 M(pro) and indicated that a Michael acceptor inhibitor is an ideal scaffold for antiviral drugs.
-Authors: Cui, W., Cui, S.S.
+The crystal structure of main protease from mouse hepatitis virus A59 in complex with an inhibitor.,Cui W, Cui S, Chen C, Chen X, Wang Z, Yang H, Zhang L Biochem Biophys Res Commun. 2019 Apr 16;511(4):794-799. doi:, 10.1016/j.bbrc.2019.02.105. Epub 2019 Mar 2. PMID:30833083<ref>PMID:30833083</ref>
-Description: The Crystal Structure of Main Protease from Mouse Hepatitis Virus A59 in Complex with an inhibitor
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Cui, S.S]]
+<div class="pdbe-citations 6jij" style="background-color:#fffaf0;"></div>
-[[Category: Cui, W]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Large Structures]]
+[[Category: Murine hepatitis virus strain A59]]
+[[Category: Synthetic construct]]
+[[Category: Cui SS]]
+[[Category: Cui W]]

6jij

From Proteopedia

Current revision

The Crystal Structure of Main Protease from Mouse Hepatitis Virus A59 in Complex with an inhibitor

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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