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2gtb

From Proteopedia

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[[Image:2gtb.jpg|left|200px]]
 
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{{Structure
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==Crystal structure of SARS coronavirus main peptidase (with an additional Ala at the N-terminus of each protomer) inhibited by an aza-peptide epoxide in the space group P43212==
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|PDB= 2gtb |SIZE=350|CAPTION= <scene name='initialview01'>2gtb</scene>, resolution 2.00&Aring;
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<StructureSection load='2gtb' size='340' side='right'caption='[[2gtb]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
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|SITE=
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== Structural highlights ==
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|LIGAND= <scene name='pdbligand=AZP:(5S,8S,14R)-ETHYL+11-(3-AMINO-3-OXOPROPYL)-8-BENZYL-14-HYDROXY-5-ISOBUTYL-3,6,9,12-TETRAOXO-1-PHENYL-2-OXA-4,7,10,11-TETRAAZAPENTADECAN-15-OATE'>AZP</scene> and <scene name='pdbligand=ACY:ACETIC ACID'>ACY</scene>
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<table><tr><td colspan='2'>[[2gtb]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Cvhsa Cvhsa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2GTB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2GTB FirstGlance]. <br>
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|ACTIVITY=
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACY:ACETIC+ACID'>ACY</scene>, <scene name='pdbligand=AZP:(5S,8S,14R)-ETHYL+11-(3-AMINO-3-OXOPROPYL)-8-BENZYL-14-HYDROXY-5-ISOBUTYL-3,6,9,12-TETRAOXO-1-PHENYL-2-OXA-4,7,10,11-TETRAAZAPENTADECAN-15-OATE'>AZP</scene></td></tr>
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|GENE=
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[2gt7|2gt7]], [[2gt8|2gt8]]</div></td></tr>
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}}
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2gtb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2gtb OCA], [https://pdbe.org/2gtb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2gtb RCSB], [https://www.ebi.ac.uk/pdbsum/2gtb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2gtb ProSAT]</span></td></tr>
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</table>
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== Function ==
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[[https://www.uniprot.org/uniprot/R1AB_CVHSA 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).<ref>PMID:17024178</ref> <ref>PMID:17692280</ref> <ref>PMID:19369340</ref> 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.<ref>PMID:17024178</ref> <ref>PMID:17692280</ref> <ref>PMID:19369340</ref> 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.<ref>PMID:17024178</ref> <ref>PMID:17692280</ref> <ref>PMID:19369340</ref> 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.<ref>PMID:17024178</ref> <ref>PMID:17692280</ref> <ref>PMID:19369340</ref> The exoribonuclease acts on both ssRNA and dsRNA in a 3' to 5' direction.<ref>PMID:17024178</ref> <ref>PMID:17692280</ref> <ref>PMID:19369340</ref> Nsp7-nsp8 hexadecamer may possibly confer processivity to the polymerase, maybe by binding to dsRNA or by producing primers utilized by the latter.<ref>PMID:17024178</ref> <ref>PMID:17692280</ref> <ref>PMID:19369340</ref> Nsp9 is a ssRNA-binding protein.<ref>PMID:17024178</ref> <ref>PMID:17692280</ref> <ref>PMID:19369340</ref> NendoU is a Mn(2+)-dependent, uridylate-specific enzyme, which leaves 2'-3'-cyclic phosphates 5' to the cleaved bond.<ref>PMID:17024178</ref> <ref>PMID:17692280</ref> <ref>PMID:19369340</ref>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/gt/2gtb_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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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=2gtb ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The SARS coronavirus main peptidase (SARS-CoV M(pro)) plays an essential role in the life-cycle of the virus and is a primary target for the development of anti-SARS agents. Here, we report the crystal structure of M(pro) at a resolution of 1.82 Angstroms, in space group P2(1) at pH 6.0. In contrast to the previously reported structure of M(pro) in the same space group at the same pH, the active sites and the S1 specificity pockets of both protomers in the structure of M(pro) reported here are in the catalytically competent conformation, suggesting their conformational flexibility. We report two crystal structures of M(pro) having an additional Ala at the N terminus of each protomer (M(+A(-1))(pro)), both at a resolution of 2.00 Angstroms, in space group P4(3)2(1)2: one unbound and one bound by a substrate-like aza-peptide epoxide (APE). In the unbound form, the active sites and the S1 specificity pockets of both protomers of M(+A(-1))(pro) are observed in a collapsed (catalytically incompetent) conformation; whereas they are in an open (catalytically competent) conformation in the APE-bound form. The observed conformational flexibility of the active sites and the S1 specificity pockets suggests that these parts of M(pro) exist in dynamic equilibrium. The structural data further suggest that the binding of APE to M(pro) follows an induced-fit model. The substrate likely also binds in an induced-fit manner in a process that may help drive the catalytic cycle.
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'''Crystal structure of SARS coronavirus main peptidase (with an additional Ala at the N-terminus of each protomer) inhibited by an aza-peptide epoxide in the space group P43212'''
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Crystal structures reveal an induced-fit binding of a substrate-like Aza-peptide epoxide to SARS coronavirus main peptidase.,Lee TW, Cherney MM, Liu J, James KE, Powers JC, Eltis LD, James MN J Mol Biol. 2007 Feb 23;366(3):916-32. Epub 2006 Dec 2. PMID:17196984<ref>PMID:17196984</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 2gtb" style="background-color:#fffaf0;"></div>
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==Overview==
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==See Also==
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The SARS coronavirus main peptidase (SARS-CoV M(pro)) plays an essential role in the life-cycle of the virus and is a primary target for the development of anti-SARS agents. Here, we report the crystal structure of M(pro) at a resolution of 1.82 Angstroms, in space group P2(1) at pH 6.0. In contrast to the previously reported structure of M(pro) in the same space group at the same pH, the active sites and the S1 specificity pockets of both protomers in the structure of M(pro) reported here are in the catalytically competent conformation, suggesting their conformational flexibility. We report two crystal structures of M(pro) having an additional Ala at the N terminus of each protomer (M(+A(-1))(pro)), both at a resolution of 2.00 Angstroms, in space group P4(3)2(1)2: one unbound and one bound by a substrate-like aza-peptide epoxide (APE). In the unbound form, the active sites and the S1 specificity pockets of both protomers of M(+A(-1))(pro) are observed in a collapsed (catalytically incompetent) conformation; whereas they are in an open (catalytically competent) conformation in the APE-bound form. The observed conformational flexibility of the active sites and the S1 specificity pockets suggests that these parts of M(pro) exist in dynamic equilibrium. The structural data further suggest that the binding of APE to M(pro) follows an induced-fit model. The substrate likely also binds in an induced-fit manner in a process that may help drive the catalytic cycle.
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*[[Virus protease 3D structures|Virus protease 3D structures]]
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== References ==
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==About this Structure==
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<references/>
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2GTB is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Sars_coronavirus Sars coronavirus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2GTB OCA].
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__TOC__
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</StructureSection>
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==Reference==
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[[Category: Cvhsa]]
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Crystal structures reveal an induced-fit binding of a substrate-like Aza-peptide epoxide to SARS coronavirus main peptidase., Lee TW, Cherney MM, Liu J, James KE, Powers JC, Eltis LD, James MN, J Mol Biol. 2007 Feb 23;366(3):916-32. Epub 2006 Dec 2. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17196984 17196984]
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[[Category: Large Structures]]
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[[Category: Sars coronavirus]]
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[[Category: Cherney, M M]]
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[[Category: Single protein]]
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[[Category: Huitema, C]]
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[[Category: Cherney, M M.]]
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[[Category: James, K E]]
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[[Category: Huitema, C.]]
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[[Category: Lee, T W]]
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[[Category: James, K E.]]
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[[Category: Liu, J]]
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[[Category: Lee, T W.]]
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[[Category: Powers, J C]]
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[[Category: Liu, J.]]
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[[Category: Powers, J C.]]
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[[Category: ACY]]
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[[Category: AZP]]
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[[Category: 3c-like]]
[[Category: 3c-like]]
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[[Category: alpha-helical domain]]
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[[Category: Alpha-helical domain]]
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[[Category: catalytic dyad]]
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[[Category: Catalytic dyad]]
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[[Category: chymotrypsin-like fold]]
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[[Category: Chymotrypsin-like fold]]
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[[Category: cysteine peptidase]]
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[[Category: Cysteine peptidase]]
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[[Category: dimer]]
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[[Category: Dimer]]
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[[Category: long loop]]
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[[Category: Hydrolase]]
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[[Category: n-finger]]
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[[Category: Long loop]]
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[[Category: specificity pocket]]
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[[Category: N-finger]]
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[[Category: Specificity pocket]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 17:08:48 2008''
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Current revision

Crystal structure of SARS coronavirus main peptidase (with an additional Ala at the N-terminus of each protomer) inhibited by an aza-peptide epoxide in the space group P43212

PDB ID 2gtb

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