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2whi

From Proteopedia

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Current revision

Crystal structure of Mycobacterium Tuberculosis Glutamine Synthetase in complex with a purine analogue inhibitor and L-methionine-S- sulfoximine phosphate.

Structural highlights

2whi is a 6 chain structure with sequence from Mycobacterium tuberculosis H37Rv. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.2Å
Ligands:	, , , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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).^[1] ^[2] ^[3] ^[4]

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 PubMed

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.

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^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Harth G, Zamecnik PC, Tang JY, Tabatadze D, Horwitz MA. Treatment of Mycobacterium tuberculosis with antisense oligonucleotides to glutamine synthetase mRNA inhibits glutamine synthetase activity, formation of the poly-L-glutamate/glutamine cell wall structure, and bacterial replication. Proc Natl Acad Sci U S A. 2000 Jan 4;97(1):418-23. PMID:10618433 doi:10.1073/pnas.97.1.418
↑ Tullius MV, Harth G, Horwitz MA. Glutamine synthetase GlnA1 is essential for growth of Mycobacterium tuberculosis in human THP-1 macrophages and guinea pigs. Infect Immun. 2003 Jul;71(7):3927-36. PMID:12819079 doi:10.1128/IAI.71.7.3927-3936.2003
↑ Harth G, Clemens DL, Horwitz MA. Glutamine synthetase of Mycobacterium tuberculosis: extracellular release and characterization of its enzymatic activity. Proc Natl Acad Sci U S A. 1994 Sep 27;91(20):9342-6. PMID:7937767 doi:10.1073/pnas.91.20.9342
↑ Harth G, Horwitz MA. Expression and efficient export of enzymatically active Mycobacterium tuberculosis glutamine synthetase in Mycobacterium smegmatis and evidence that the information for export is contained within the protein. J Biol Chem. 1997 Sep 5;272(36):22728-35. PMID:9278431 doi:10.1074/jbc.272.36.22728
↑ Nilsson MT, Krajewski WW, Yellagunda S, Prabhumurthy S, Chamarahally GN, Siddamadappa C, Srinivasa BR, Yahiaoui S, Larhed M, Karlen A, Jones TA, Mowbray SL. Structural basis for the inhibition of Mycobacterium tuberculosis glutamine synthetase by novel ATP-competitive inhibitors. J Mol Biol. 2009 Oct 23;393(2):504-13. Epub 2009 Aug 18. PMID:19695264 doi:10.1016/j.jmb.2009.08.028

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2whi"

@@ Line 1: / Line 1: @@
-==CRYSTAL STRUCTURE OF MYCOBACTERIUM TUBERCULOSIS GLUTAMINE SYNTHETASE IN COMPLEX WITH A PURINE ANALOGUE INHIBITOR AND L-METHIONINE-S-SULFOXIMINE PHOSPHATE.==
-<StructureSection load='2whi' size='340' side='right' caption='[[2whi]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
+==Crystal structure of Mycobacterium Tuberculosis Glutamine Synthetase in complex with a purine analogue inhibitor and L-methionine-S- sulfoximine phosphate.==
+<StructureSection load='2whi' size='340' side='right'caption='[[2whi]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2whi]] is a 6 chain structure with sequence 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=2WHI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2WHI FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2whi]] is a 6 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=2WHI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2WHI FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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=1PE:PENTAETHYLENE+GLYCOL'>1PE</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=P3S:L-METHIONINE-S-SULFOXIMINE+PHOSPHATE'>P3S</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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]] 2.2&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1hto|1hto]], [[1htq|1htq]], [[2wgs|2wgs]], [[2bvc|2bvc]]</td></tr>
+<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=1PE:PENTAETHYLENE+GLYCOL'>1PE</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=P3S:L-METHIONINE-S-SULFOXIMINE+PHOSPHATE'>P3S</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Glutamate--ammonia_ligase Glutamate--ammonia ligase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.3.1.2 6.3.1.2] </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=2whi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2whi OCA], [https://pdbe.org/2whi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2whi RCSB], [https://www.ebi.ac.uk/pdbsum/2whi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2whi 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=2whi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2whi OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2whi RCSB], [http://www.ebi.ac.uk/pdbsum/2whi PDBsum]</span></td></tr>
 </table>
+== Function ==
+[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>
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
 Check<jmol>
   <jmolCheckbox>
-    <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/wh/2whi_consurf.spt"</scriptWhenChecked>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/wh/2whi_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
   </jmolCheckbox>
-</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/chain_selection.php?pdb_ID=2ata 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=2whi ConSurf].
 <div style="clear:both"></div>
 <div style="background-color:#fffaf0;">
@@ Line 26: / Line 28: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 2whi" style="background-color:#fffaf0;"></div>
 ==See Also==
-*[[Glutamine Synthase|Glutamine Synthase]]
+*[[Glutamine synthetase 3D structures|Glutamine synthetase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Glutamate--ammonia ligase]]
+[[Category: Large Structures]]
-[[Category: Mycobacterium tuberculosis]]
+[[Category: Mycobacterium tuberculosis H37Rv]]
-[[Category: Jones, T A]]
+[[Category: Jones TA]]
-[[Category: Krajewski, W W]]
+[[Category: Krajewski WW]]
-[[Category: Mowbray, S L]]
+[[Category: Mowbray SL]]
-[[Category: Nilsson, M T]]
+[[Category: Nilsson MT]]
-[[Category: Atp-binding]]
-[[Category: Glna1]]
-[[Category: Ligase]]
-[[Category: Mt2278]]
-[[Category: Nucleotide-binding]]
-[[Category: Purine analogue]]
-[[Category: Rv2220]]
-[[Category: Synthetase]]
-[[Category: Taut state]]
-[[Category: Transition state mimic]]

2whi

From Proteopedia

Current revision

Crystal structure of Mycobacterium Tuberculosis Glutamine Synthetase in complex with a purine analogue inhibitor and L-methionine-S- sulfoximine phosphate.

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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