4ylu: Difference between revisions
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<StructureSection load='4ylu' size='340' side='right' caption='[[4ylu]], [[Resolution|resolution]] 2.10Å' scene=''> | <StructureSection load='4ylu' size='340' side='right' caption='[[4ylu]], [[Resolution|resolution]] 2.10Å' 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 [http://en.wikipedia.org/wiki/Mers Mers]. 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> | ||
</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='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> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4rsp|4rsp]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4rsp|4rsp]]</td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">orf1ab ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1335626 MERS])</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://pdbe.org/4ylu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ylu RCSB], [http://www.ebi.ac.uk/pdbsum/4ylu PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ylu ProSAT]</span></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://pdbe.org/4ylu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ylu RCSB], [http://www.ebi.ac.uk/pdbsum/4ylu PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ylu ProSAT]</span></td></tr> | ||
</table> | </table> | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Mers]] | |||
[[Category: Mesecar, A D]] | [[Category: Mesecar, A D]] | ||
[[Category: Tomar, S]] | [[Category: Tomar, S]] | ||
[[Category: Hydrolase-hydrolase inhibitor complex]] | [[Category: Hydrolase-hydrolase inhibitor complex]] | ||
[[Category: Protease]] | [[Category: Protease]] | ||
Revision as of 18:51, 15 November 2017
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
Publication Abstract from PubMedAll 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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