2wgs

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{{Seed}}
 
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[[Image:2wgs.jpg|left|200px]]
 
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==Crystal structure of Mycobacterium Tuberculosis Glutamine Synthetase in complex with a purine analogue inhibitor.==
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The line below this paragraph, containing "STRUCTURE_2wgs", creates the "Structure Box" on the page.
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<StructureSection load='2wgs' size='340' side='right'caption='[[2wgs]], [[Resolution|resolution]] 2.55&Aring;' scene=''>
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You may change the PDB parameter (which sets the PDB file loaded into the applet)
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== Structural highlights ==
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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<table><tr><td colspan='2'>[[2wgs]] is a 12 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_H37Rv Mycobacterium tuberculosis H37Rv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2WGS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2WGS FirstGlance]. <br>
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or leave the SCENE parameter empty for the default display.
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.55&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1AZ:1-(3,4-DICHLOROBENZYL)-3,7-DIMETHYL-8-MORPHOLIN-4-YL-3,7-DIHYDRO-1H-PURINE-2,6-DIONE'>1AZ</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr>
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{{STRUCTURE_2wgs| PDB=2wgs | SCENE= }}
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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=2wgs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2wgs OCA], [https://pdbe.org/2wgs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2wgs RCSB], [https://www.ebi.ac.uk/pdbsum/2wgs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2wgs ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/GLN1B_MYCTU GLN1B_MYCTU] Involved in nitrogen metabolism via ammonium assimilation. Catalyzes the ATP-dependent biosynthesis of glutamine from glutamate and ammonia (PubMed:7937767, PubMed:12819079). Also able to use GTP (PubMed:7937767). D-glutamate is a poor substrate, and DL-glutamate shows about 50% of the standard specific activity (PubMed:7937767). Also plays a key role in controlling the ammonia levels within infected host cells and so contributes to the pathogens capacity to inhibit phagosome acidification and phagosome-lysosome fusion (PubMed:7937767, PubMed:12819079). Involved in cell wall biosynthesis via the production of the major component poly-L-glutamine (PLG) (PubMed:7937767, PubMed:10618433). PLG synthesis in the cell wall occurs only in nitrogen limiting conditions and on the contrary high nitrogen conditions inhibit PLG synthesis (Probable).<ref>PMID:10618433</ref> <ref>PMID:12819079</ref> <ref>PMID:7937767</ref> <ref>PMID:9278431</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/wg/2wgs_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=2wgs 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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Glutamine synthetase (GS, EC 6.3.1.2; also known as gamma-glutamyl:ammonia ligase) catalyzes the ATP-dependent condensation of glutamate and ammonia to form glutamine. The enzyme has essential roles in different tissues and species, which have led to its consideration as a drug or an herbicide target. In this article, we describe studies aimed at the discovery of new antimicrobial agents targeting Mycobacterium tuberculosis, the causative pathogen of tuberculosis. A number of distinct classes of GS inhibitors with an IC(50) of micromolar value or better were identified via high-throughput screening. A commercially available purine analogue similar to one of the clusters identified (the diketopurines), 1-[(3,4-dichlorophenyl)methyl]-3,7-dimethyl-8-morpholin-4-yl-purine-2,6-di one, was also shown to inhibit the enzyme, with a measured IC(50) of 2.5+/-0.4 microM. Two X-ray structures are presented: one is a complex of the enzyme with the purine analogue alone (2.55-A resolution), and the other includes the compound together with methionine sulfoximine phosphate, magnesium and phosphate (2.2-A resolution). The former represents a relaxed, inactive conformation of the enzyme, while the latter is a taut, active one. These structures show that the compound binds at the same position in the nucleotide site, regardless of the conformational state. The ATP-binding site of the human enzyme differs substantially, explaining why it has an approximately 60-fold lower affinity for this compound than the bacterial GS. As part of this work, we devised a new synthetic procedure for generating l-(SR)-methionine sulfoximine phosphate from l-(SR)-methionine sulfoximine, which will facilitate future investigations of novel GS inhibitors.
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===CRYSTAL STRUCTURE OF MYCOBACTERIUM TUBERCULOSIS GLUTAMINE SYNTHETASE IN COMPLEX WITH A PURINE ANALOGUE INHIBITOR.===
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Structural basis for the inhibition of Mycobacterium tuberculosis glutamine synthetase by novel ATP-competitive inhibitors.,Nilsson MT, Krajewski WW, Yellagunda S, Prabhumurthy S, Chamarahally GN, Siddamadappa C, Srinivasa BR, Yahiaoui S, Larhed M, Karlen A, Jones TA, Mowbray SL J Mol Biol. 2009 Oct 23;393(2):504-13. Epub 2009 Aug 18. PMID:19695264<ref>PMID:19695264</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 2wgs" style="background-color:#fffaf0;"></div>
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==See Also==
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The line below this paragraph, {{ABSTRACT_PUBMED_19695264}}, adds the Publication Abstract to the page
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*[[Glutamine synthetase 3D structures|Glutamine synthetase 3D structures]]
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(as it appears on PubMed at http://www.pubmed.gov), where 19695264 is the PubMed ID number.
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== References ==
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<references/>
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{{ABSTRACT_PUBMED_19695264}}
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__TOC__
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</StructureSection>
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==About this Structure==
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[[Category: Large Structures]]
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2WGS is a 12 chains structure of sequences from [http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2WGS OCA].
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[[Category: Mycobacterium tuberculosis H37Rv]]
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[[Category: Jones TA]]
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==Reference==
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[[Category: Krajewski WW]]
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<ref group="xtra">PMID:19695264</ref><ref group="xtra">PMID:16027359</ref><references group="xtra"/>
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[[Category: Mowbray SL]]
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[[Category: Glutamate--ammonia ligase]]
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[[Category: Nilsson MT]]
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[[Category: Mycobacterium tuberculosis]]
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[[Category: Jones, T A.]]
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[[Category: Krajewski, W W.]]
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[[Category: Mowbray, S L.]]
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[[Category: Nilsson, M T.]]
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[[Category: Cytoplasm]]
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[[Category: Glna1]]
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[[Category: Ligase]]
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[[Category: Mt2278]]
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[[Category: Nucleotide-binding]]
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[[Category: Purine analogue]]
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[[Category: Relaxed state]]
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[[Category: Rv2220]]
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[[Category: Synthetase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Sep 3 16:00:35 2009''
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Current revision

Crystal structure of Mycobacterium Tuberculosis Glutamine Synthetase in complex with a purine analogue inhibitor.

PDB ID 2wgs

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