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| | ==Mycobacterium tuberculosis CysM in complex with the Urea-scaffold inhibitor 2 [3-(3-([1,1'-biphenyl]-3-yl)ureido)benzoic acid]== | | ==Mycobacterium tuberculosis CysM in complex with the Urea-scaffold inhibitor 2 [3-(3-([1,1'-biphenyl]-3-yl)ureido)benzoic acid]== |
| - | <StructureSection load='5i7r' size='340' side='right' caption='[[5i7r]], [[Resolution|resolution]] 1.73Å' scene=''> | + | <StructureSection load='5i7r' size='340' side='right'caption='[[5i7r]], [[Resolution|resolution]] 1.73Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5i7r]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5I7R OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5I7R FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5i7r]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5I7R OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5I7R FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=68W:3-{[([1,1-BIPHENYL]-3-YL)CARBAMOYL]AMINO}BENZOIC+ACID'>68W</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=PLP:PYRIDOXAL-5-PHOSPHATE'>PLP</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]] 1.73Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3dki|3dki]], [[3fgp|3fgp]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=68W:3-{[([1,1-BIPHENYL]-3-YL)CARBAMOYL]AMINO}BENZOIC+ACID'>68W</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=PLP:PYRIDOXAL-5-PHOSPHATE'>PLP</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/[CysO_sulfur-carrier_protein]-thiocarboxylate-dependent_cysteine_synthase [CysO sulfur-carrier protein]-thiocarboxylate-dependent cysteine synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.5.1.113 2.5.1.113] </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=5i7r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5i7r OCA], [https://pdbe.org/5i7r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5i7r RCSB], [https://www.ebi.ac.uk/pdbsum/5i7r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5i7r 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=5i7r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5i7r OCA], [http://pdbe.org/5i7r PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5i7r RCSB], [http://www.ebi.ac.uk/pdbsum/5i7r PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5i7r ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CYSM_MYCTU CYSM_MYCTU]] Catalyzes the formation of a covalent CysO-cysteine adduct via a sulfur transfer, using the thiocarboxylated sulfur carrier protein CysO-COSH as sulfur donor and O-phospho-L-serine (OPS) as sulfur acceptor. Can also use sodium sulfide as sulfur donor in vitro, albeit with less efficiency, but not thiosulfate or thio-nitro-benzoate. O-acetylserine (OAS) is a very poor substrate in comparison with OPS. May be of particular importance for cysteine biosynthesis in the persistent phase of M.tuberculosis.<ref>PMID:18842002</ref> <ref>PMID:18799456</ref> | + | [https://www.uniprot.org/uniprot/CYSM_MYCTU CYSM_MYCTU] Catalyzes the formation of a covalent CysO-cysteine adduct via a sulfur transfer, using the thiocarboxylated sulfur carrier protein CysO-COSH as sulfur donor and O-phospho-L-serine (OPS) as sulfur acceptor. Can also use sodium sulfide as sulfur donor in vitro, albeit with less efficiency, but not thiosulfate or thio-nitro-benzoate. O-acetylserine (OAS) is a very poor substrate in comparison with OPS. May be of particular importance for cysteine biosynthesis in the persistent phase of M.tuberculosis.<ref>PMID:18842002</ref> <ref>PMID:18799456</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Maric, S]] | + | [[Category: Large Structures]] |
| - | [[Category: Schneider, G]]
| + | |
| - | [[Category: Schnell, R]]
| + | |
| - | [[Category: Cysteine biosynthesis]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Lyase]]
| + | |
| | [[Category: Mycobacterium tuberculosis]] | | [[Category: Mycobacterium tuberculosis]] |
| - | [[Category: Sulphur metabolism]] | + | [[Category: Maric S]] |
| | + | [[Category: Schneider G]] |
| | + | [[Category: Schnell R]] |
| Structural highlights
Function
CYSM_MYCTU Catalyzes the formation of a covalent CysO-cysteine adduct via a sulfur transfer, using the thiocarboxylated sulfur carrier protein CysO-COSH as sulfur donor and O-phospho-L-serine (OPS) as sulfur acceptor. Can also use sodium sulfide as sulfur donor in vitro, albeit with less efficiency, but not thiosulfate or thio-nitro-benzoate. O-acetylserine (OAS) is a very poor substrate in comparison with OPS. May be of particular importance for cysteine biosynthesis in the persistent phase of M.tuberculosis.[1] [2]
Publication Abstract from PubMed
Cysteine is an important amino acid in the redox defense of Mycobacterium tuberculosis, primarily as a building block of mycothiol. Genetic studies have implicated de novo cysteine biosynthesis in pathogen survival in infected macrophages, in particular for persistent M. tuberculosis. Here, we report on the identification and characterization of potent inhibitors of CysM, a critical enzyme in cysteine biosynthesis during dormancy. A screening campaign of 17312 compounds identified ligands that bind to the active site with micromolar affinity. These were characterized in terms of their inhibitory potencies and structure-activity relationships through hit expansion guided by three-dimensional structures of enzyme-inhibitor complexes. The top compound binds to CysM with 300 nM affinity and displays selectivity over the mycobacterial homologues CysK1 and CysK2. Notably, two inhibitors show significant potency in a nutrient-starvation model of dormancy of Mycobacterium tuberculosis, with little or no cytotoxicity toward mammalian cells.
Inhibitors of the Cysteine Synthase CysM with Antibacterial Potency against Dormant Mycobacterium tuberculosis.,Brunner K, Maric S, Reshma RS, Almqvist H, Seashore-Ludlow B, Gustavsson AL, Poyraz O, Yogeeswari P, Lundback T, Vallin M, Sriram D, Schnell R, Schneider G J Med Chem. 2016 Jul 28;59(14):6848-59. doi: 10.1021/acs.jmedchem.6b00674. Epub, 2016 Jul 13. PMID:27379713[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ O'Leary SE, Jurgenson CT, Ealick SE, Begley TP. O-phospho-L-serine and the thiocarboxylated sulfur carrier protein CysO-COSH are substrates for CysM, a cysteine synthase from Mycobacterium tuberculosis. Biochemistry. 2008 Nov 4;47(44):11606-15. doi: 10.1021/bi8013664. Epub 2008 Oct, 9. PMID:18842002 doi:http://dx.doi.org/10.1021/bi8013664
- ↑ Agren D, Schnell R, Oehlmann W, Singh M, Schneider G. Cysteine synthase (CysM) of Mycobacterium tuberculosis is an O-phosphoserine sulfhydrylase: evidence for an alternative cysteine biosynthesis pathway in mycobacteria. J Biol Chem. 2008 Nov 14;283(46):31567-74. Epub 2008 Sep 16. PMID:18799456 doi:10.1074/jbc.M804877200
- ↑ Brunner K, Maric S, Reshma RS, Almqvist H, Seashore-Ludlow B, Gustavsson AL, Poyraz O, Yogeeswari P, Lundback T, Vallin M, Sriram D, Schnell R, Schneider G. Inhibitors of the Cysteine Synthase CysM with Antibacterial Potency against Dormant Mycobacterium tuberculosis. J Med Chem. 2016 Jul 28;59(14):6848-59. doi: 10.1021/acs.jmedchem.6b00674. Epub, 2016 Jul 13. PMID:27379713 doi:http://dx.doi.org/10.1021/acs.jmedchem.6b00674
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