2gx4: Difference between revisions
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==Crystal structure of SARS coronavirus 3CL protease inhibitor complex== | ==Crystal structure of SARS coronavirus 3CL protease inhibitor complex== | ||
<StructureSection load='2gx4' size='340' side='right' caption='[[2gx4]], [[Resolution|resolution]] 1.93Å' scene=''> | <StructureSection load='2gx4' size='340' side='right'caption='[[2gx4]], [[Resolution|resolution]] 1.93Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[2gx4]] is a 1 chain structure | <table><tr><td colspan='2'>[[2gx4]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2GX4 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=2GX4 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NOL:N-[(BENZYLOXY)CARBONYL]-O-(TERT-BUTYL)-L-THREONYL-3-CYCLOHEXYL-N-[(1S)-2-HYDROXY-1-{[(3S)-2-OXOPYRROLIDIN-3-YL]METHYL}ETHYL]-L-ALANINAMIDE'>NOL</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NOL:N-[(BENZYLOXY)CARBONYL]-O-(TERT-BUTYL)-L-THREONYL-3-CYCLOHEXYL-N-[(1S)-2-HYDROXY-1-{[(3S)-2-OXOPYRROLIDIN-3-YL]METHYL}ETHYL]-L-ALANINAMIDE'>NOL</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1z1i|1z1i]], [[1z1j|1z1j]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1z1i|1z1i]], [[1z1j|1z1j]]</td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http:// | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=2gx4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2gx4 OCA], [http://pdbe.org/2gx4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2gx4 RCSB], [http://www.ebi.ac.uk/pdbsum/2gx4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2gx4 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2gx4 ConSurf]. | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2gx4 ConSurf]. | ||
<div style="clear:both"></div> | <div style="clear:both"></div> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
A potent SARS coronavirus (CoV) 3CL protease inhibitor (TG-0205221, Ki = 53 nM) has been developed. TG-0205221 showed remarkable activity against SARS CoV and human coronavirus (HCoV) 229E replications by reducing the viral titer by 4.7 log (at 5 microM) for SARS CoV and 5.2 log (at 1.25 microM) for HCoV 229E. The crystal structure of TG-0205221 (resolution = 1.93 A) has revealed a unique binding mode comprising a covalent bond, hydrogen bonds, and numerous hydrophobic interactions. Structural comparisons between TG-0205221 and a natural peptide substrate were also discussed. This information may be applied toward the design of other 3CL protease inhibitors. | |||
Synthesis, crystal structure, structure-activity relationships, and antiviral activity of a potent SARS coronavirus 3CL protease inhibitor.,Yang S, Chen SJ, Hsu MF, Wu JD, Tseng CT, Liu YF, Chen HC, Kuo CW, Wu CS, Chang LW, Chen WC, Liao SY, Chang TY, Hung HH, Shr HL, Liu CY, Huang YA, Chang LY, Hsu JC, Peters CJ, Wang AH, Hsu MC J Med Chem. 2006 Aug 10;49(16):4971-80. doi: 10.1021/jm0603926. PMID:16884309<ref>PMID:16884309</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 2gx4" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
*[[SARS Coronavirus Main Proteinase|SARS Coronavirus Main Proteinase]] | *[[SARS Coronavirus Main Proteinase|SARS Coronavirus Main Proteinase]] | ||
*[[ | *[[Virus proteases 3D strutures|Virus proteases 3D strutures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Hsu, M F]] | [[Category: Hsu, M F]] | ||
[[Category: Wang, A H.J]] | [[Category: Wang, A H.J]] | ||
Revision as of 10:06, 8 April 2020
Structural highlights
Function[R1AB_CVHSA] 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 (By similarity).[1] [2] [3] The papain-like proteinase (PL-PRO) is responsible for the cleavages located at the N-terminus of replicase polyprotein. In addition, PL-PRO 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.[4] [5] [6] 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 (By similarity). Also contains an ADP-ribose-1-phosphate (ADRP)-binding function.[7] [8] [9] The helicase which contains a zinc finger structure displays RNA and DNA duplex-unwinding activities with 5' to 3' polarity. Its ATPase activity is strongly stimulated by poly(U), poly(dT), poly(C), poly(dA), but not by poly(G). Activity of helicase is dependent on magnesium.[10] [11] [12] The exoribonuclease acts on both ssRNA and dsRNA in a 3' to 5' direction.[13] [14] [15] Nsp7-nsp8 hexadecamer may possibly confer processivity to the polymerase, maybe by binding to dsRNA or by producing primers utilized by the latter.[16] [17] [18] Nsp9 is a ssRNA-binding protein.[19] [20] [21] NendoU is a Mn(2+)-dependent, uridylate-specific enzyme, which leaves 2'-3'-cyclic phosphates 5' to the cleaved bond.[22] [23] [24] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedA potent SARS coronavirus (CoV) 3CL protease inhibitor (TG-0205221, Ki = 53 nM) has been developed. TG-0205221 showed remarkable activity against SARS CoV and human coronavirus (HCoV) 229E replications by reducing the viral titer by 4.7 log (at 5 microM) for SARS CoV and 5.2 log (at 1.25 microM) for HCoV 229E. The crystal structure of TG-0205221 (resolution = 1.93 A) has revealed a unique binding mode comprising a covalent bond, hydrogen bonds, and numerous hydrophobic interactions. Structural comparisons between TG-0205221 and a natural peptide substrate were also discussed. This information may be applied toward the design of other 3CL protease inhibitors. Synthesis, crystal structure, structure-activity relationships, and antiviral activity of a potent SARS coronavirus 3CL protease inhibitor.,Yang S, Chen SJ, Hsu MF, Wu JD, Tseng CT, Liu YF, Chen HC, Kuo CW, Wu CS, Chang LW, Chen WC, Liao SY, Chang TY, Hung HH, Shr HL, Liu CY, Huang YA, Chang LY, Hsu JC, Peters CJ, Wang AH, Hsu MC J Med Chem. 2006 Aug 10;49(16):4971-80. doi: 10.1021/jm0603926. PMID:16884309[25] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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