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==X-ray structure of MERS-CoV nsp5 protease bound with a non-covalent inhibitor==
==X-ray structure of MERS-CoV nsp5 protease bound with a non-covalent inhibitor==
<StructureSection load='4ylu' size='340' side='right' caption='[[4ylu]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
<StructureSection load='4ylu' size='340' side='right'caption='[[4ylu]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4ylu]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4YLU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4YLU FirstGlance]. <br>
<table><tr><td colspan='2'>[[4ylu]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Middle_East_respiratory_syndrome-related_coronavirus Middle East respiratory syndrome-related coronavirus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4YLU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4YLU FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=R30:N-{4-[(1H-BENZOTRIAZOL-1-YLACETYL)(THIOPHEN-3-YLMETHYL)AMINO]PHENYL}PROPANAMIDE'>R30</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.1&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4rsp|4rsp]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=R30:N-{4-[(1H-BENZOTRIAZOL-1-YLACETYL)(THIOPHEN-3-YLMETHYL)AMINO]PHENYL}PROPANAMIDE'>R30</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=4ylu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ylu OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ylu RCSB], [http://www.ebi.ac.uk/pdbsum/4ylu PDBsum]</span></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=4ylu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ylu OCA], [https://pdbe.org/4ylu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ylu RCSB], [https://www.ebi.ac.uk/pdbsum/4ylu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ylu ProSAT]</span></td></tr>
</table>
</table>
<div style="background-color:#fffaf0;">
== Function ==
== Publication Abstract from PubMed ==
[https://www.uniprot.org/uniprot/V9TU12_MERS V9TU12_MERS] Catalytic subunit of viral RNA capping enzyme which catalyzes the RNA guanylyltransferase reaction for genomic and sub-genomic RNAs. The kinase-like NiRAN domain of NSP12 transfers RNA to the amino terminus of NSP9, forming a covalent RNA-protein intermediate. Subsequently, the NiRAN domain transfers RNA to GDP, forming the core cap structure GpppA-RNA. The NSP14 and NSP16 methyltransferases then add methyl groups to form functional cap structures.[ARBA:ARBA00034461]
All coronaviruses, including the recently emerged Middle East respiratory syndrome coronavirus (MERS-CoV) from the beta-CoV subgroup, require the proteolytic activity of nsp5 protease (aka 3C-like protease, 3CLpro) during virus replication, making it a high value target for the development of anti-coronavirus therapeutics. Kinetic studies indicate that in contrast to 3CLpro from other beta-CoV 2c members including HKU4 and HKU5, MERS-CoV 3CLpro is less efficient at processing a peptide substrate due to MERS-CoV 3CLpro being a weakly associated dimer. Conversely, HKU4, HKU5 and SARS-CoV 3CLpro enzymes are tightly associated dimers. AUC studies support that MERS-CoV 3CLpro is a weakly associated dimer (Kd ~ 52 mu) with a slow off-rate. Peptidomimetic inhibitors of MERS-CoV 3CLpro were synthesized and utilized in AUC experiments and demonstrate that MERS-CoV 3CLpro undergoes significant ligand-induced dimerization. Kinetic studies also revealed that designed reversible inhibitors act as activators at low compound concentration as a result of induced dimerization. Primary sequence comparisons and X-ray structural analyses of two MERS-CoV 3CLpro-inhibitor complexes, determined to 1.6 A, reveal remarkable structural similarity of the dimer interface with 3CLpro from HKU4-CoV and HKU5-CoV. Despite this structural similarity, substantial differences in the dimerization ability suggest that long-range interactions by the non-conserved amino acids distant from the dimer interface may control MERS-CoV 3CLpro dimerization. Activation of MERS-CoV 3CLpro through ligand-induced dimerization appears to be unique within the genogroup 2c and may potentially increase the complexity in the development of MERS-CoV 3CLpro inhibitors as antiviral agents.
 
Ligand-induced dimerization of MERS coronavirus nsp5 protease (3CLpro): implications for nsp5 regulation and the development of antivirals.,Tomar S, Johnston ML, St John SE, Osswald HL, Nyalapatla PR, Paul LN, Ghosh AK, Denison MR, Mesecar AD J Biol Chem. 2015 Jun 8. pii: jbc.M115.651463. PMID:26055715<ref>PMID:26055715</ref>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
==See Also==
</div>
*[[Virus protease 3D structures|Virus protease 3D structures]]
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Mesecar, A D]]
[[Category: Large Structures]]
[[Category: Tomar, S]]
[[Category: Middle East respiratory syndrome-related coronavirus]]
[[Category: Hydrolase-hydrolase inhibitor complex]]
[[Category: Mesecar AD]]
[[Category: Protease]]
[[Category: Tomar S]]

Latest revision as of 16:03, 1 March 2024

X-ray structure of MERS-CoV nsp5 protease bound with a non-covalent inhibitorX-ray structure of MERS-CoV nsp5 protease bound with a non-covalent inhibitor

Structural highlights

4ylu is a 4 chain structure with sequence from Middle East respiratory syndrome-related coronavirus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.1Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

V9TU12_MERS Catalytic subunit of viral RNA capping enzyme which catalyzes the RNA guanylyltransferase reaction for genomic and sub-genomic RNAs. The kinase-like NiRAN domain of NSP12 transfers RNA to the amino terminus of NSP9, forming a covalent RNA-protein intermediate. Subsequently, the NiRAN domain transfers RNA to GDP, forming the core cap structure GpppA-RNA. The NSP14 and NSP16 methyltransferases then add methyl groups to form functional cap structures.[ARBA:ARBA00034461]

See Also

4ylu, resolution 2.10Å

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