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| | ==Crystal structure of HsaD bound to 3,5-dichlorobenzene sulphonamide== | | ==Crystal structure of HsaD bound to 3,5-dichlorobenzene sulphonamide== |
| - | <StructureSection load='5jzb' size='340' side='right' caption='[[5jzb]], [[Resolution|resolution]] 2.10Å' scene=''> | + | <StructureSection load='5jzb' size='340' side='right'caption='[[5jzb]], [[Resolution|resolution]] 2.10Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5jzb]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Myctu Myctu]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5JZB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5JZB FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5jzb]] is a 2 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=5JZB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5JZB FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6OT:3,5-DICHLOROBENZENE-1-SULFONAMIDE'>6OT</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]] 2.102Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2vf2|2vf2]], [[5jz9|5jz9]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6OT:3,5-DICHLOROBENZENE-1-SULFONAMIDE'>6OT</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">hsaD, bphD, Rv3569c ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83332 MYCTU])</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=5jzb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5jzb OCA], [https://pdbe.org/5jzb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5jzb RCSB], [https://www.ebi.ac.uk/pdbsum/5jzb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5jzb 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=5jzb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5jzb OCA], [http://pdbe.org/5jzb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5jzb RCSB], [http://www.ebi.ac.uk/pdbsum/5jzb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5jzb ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/HSAD_MYCTU HSAD_MYCTU]] Catalyzes the hydrolysis of a carbon-carbon bond in 4,5: 9,10-diseco-3-hydroxy-5,9,17-trioxoandrosta-1(10),2-diene-4-oate (4,9-DSHA) to yield 9,17-dioxo-1,2,3,4,10,19-hexanorandrostan-5-oate (DOHNAA) and 2-hydroxy-hexa-2,4-dienoate (HHD). Is also able to catalyze the hydrolysis of 2-hydroxy-6-oxo-6-phenylhexa-2,4-dienoic acid (HOPDA) and the synthetic analog 8-(2-chlorophenyl)-2-hydroxy-5-methyl-6-oxoocta-2,4-dienoic acid (HOPODA).<ref>PMID:19875455</ref> | + | [https://www.uniprot.org/uniprot/HSAD_MYCTU HSAD_MYCTU] Catalyzes the hydrolysis of a carbon-carbon bond in 4,5: 9,10-diseco-3-hydroxy-5,9,17-trioxoandrosta-1(10),2-diene-4-oate (4,9-DSHA) to yield 9,17-dioxo-1,2,3,4,10,19-hexanorandrostan-5-oate (DOHNAA) and 2-hydroxy-hexa-2,4-dienoate (HHD). Is also able to catalyze the hydrolysis of 2-hydroxy-6-oxo-6-phenylhexa-2,4-dienoic acid (HOPDA) and the synthetic analog 8-(2-chlorophenyl)-2-hydroxy-5-methyl-6-oxoocta-2,4-dienoic acid (HOPODA).<ref>PMID:19875455</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: Myctu]] | + | [[Category: Large Structures]] |
| - | [[Category: Abihammad, A]] | + | [[Category: Mycobacterium tuberculosis H37Rv]] |
| - | [[Category: Ballet, R]] | + | [[Category: Abihammad A]] |
| - | [[Category: Bhakta, S]] | + | [[Category: Ballet R]] |
| - | [[Category: Ciulli, A]] | + | [[Category: Bhakta S]] |
| - | [[Category: Eleftheriadou, O]] | + | [[Category: Ciulli A]] |
| - | [[Category: Evangelopoulos, D]] | + | [[Category: Eleftheriadou O]] |
| - | [[Category: Halman, A]] | + | [[Category: Evangelopoulos D]] |
| - | [[Category: Keany, S]] | + | [[Category: Halman A]] |
| - | [[Category: Lack, N A]] | + | [[Category: Keany S]] |
| - | [[Category: Lowe, E]] | + | [[Category: Lack NA]] |
| - | [[Category: McHugh, T D]] | + | [[Category: Lowe E]] |
| - | [[Category: Polycarpou, E]] | + | [[Category: McHugh TD]] |
| - | [[Category: Ryan, A]] | + | [[Category: Polycarpou E]] |
| - | [[Category: Sieg, C]] | + | [[Category: Ryan A]] |
| - | [[Category: Sim, E]] | + | [[Category: Sieg C]] |
| - | [[Category: Sinclair, A]] | + | [[Category: Sim E]] |
| - | [[Category: Cholesterol]]
| + | [[Category: Sinclair A]] |
| - | [[Category: Hsad]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: M. tuberculosis]]
| + | |
| - | [[Category: Mcp-hydrolase]]
| + | |
| Structural highlights
Function
HSAD_MYCTU Catalyzes the hydrolysis of a carbon-carbon bond in 4,5: 9,10-diseco-3-hydroxy-5,9,17-trioxoandrosta-1(10),2-diene-4-oate (4,9-DSHA) to yield 9,17-dioxo-1,2,3,4,10,19-hexanorandrostan-5-oate (DOHNAA) and 2-hydroxy-hexa-2,4-dienoate (HHD). Is also able to catalyze the hydrolysis of 2-hydroxy-6-oxo-6-phenylhexa-2,4-dienoic acid (HOPDA) and the synthetic analog 8-(2-chlorophenyl)-2-hydroxy-5-methyl-6-oxoocta-2,4-dienoic acid (HOPODA).[1]
Publication Abstract from PubMed
BACKGROUND AND PURPOSE: With the emergence of extensively drug-resistant tuberculosis there is a need for new anti-tubercular drugs that work through novel mechanisms of action. The meta cleavage product hydrolase, HsaD, has been demonstrated to be critical to the survival of Mycobacterium tuberculosis in macrophages and is encoded in an operon involved in cholesterol catabolism, which is identical in M. tuberculosis and M. bovis BCG. EXPERIMENTAL APPROACH: We generated a mutant strain of M. bovis BCG with a deletion of hsaD and tested its growth on cholesterol. Using a fragment based approach, over 1,000 compounds were screened by a combination of differential scanning fluorimetry, NMR spectroscopy and enzymatic assay with pure recombinant HsaD to identify potential inhibitors. We used enzymological and structural studies to investigate derivatives of inhibitors identified and to test their effects on growth of M. bovis BCG and M. tuberculosis. KEY RESULTS: The hsaD deleted strain is unable to grow on cholesterol as sole carbon source but can grow on glucose. Of seven chemically distinct "hits" from the library, two chemical classes of fragments were found to bind in the vicinity of the active siteof HsaD by X-ray crystallography. The compounds also inhibited growth of M. tuberculosis on cholesterol. The most potent inhibitor of HsaD was found also to be the best inhibitor of mycobacterial growth on cholesterol-supplemented minimal medium. CONCLUSIONS AND IMPLICATIONS: We propose that HsaD is a novel therapeutic target which should be fully exploited in order to design and discover new anti-tubercular drugs.
Investigation of the mycobacterial enzyme HsaD as a potential novel target for anti-tubercular agents using a fragment-based drug design approach.,Ryan A, Polycarpou E, Lack NA, Evangelopoulos D, Sieg C, Halman A, Bhakta S, Eleftheriadou O, McHugh TD, Keany S, Lowe ED, Ballet R, Abuhammad A, Jacobs WR Jr, Ciulli A, Sim E Br J Pharmacol. 2017 Apr 5. doi: 10.1111/bph.13810. PMID:28380256[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Lack NA, Yam KC, Lowe ED, Horsman GP, Owen RL, Sim E, Eltis LD. Characterization of a carbon-carbon hydrolase from Mycobacterium tuberculosis involved in cholesterol metabolism. J Biol Chem. 2010 Jan 1;285(1):434-43. Epub 2009 Oct 29. PMID:19875455 doi:10.1074/jbc.M109.058081
- ↑ Ryan A, Polycarpou E, Lack NA, Evangelopoulos D, Sieg C, Halman A, Bhakta S, Eleftheriadou O, McHugh TD, Keany S, Lowe ED, Ballet R, Abuhammad A, Jacobs WR Jr, Ciulli A, Sim E. Investigation of the mycobacterial enzyme HsaD as a potential novel target for anti-tubercular agents using a fragment-based drug design approach. Br J Pharmacol. 2017 Apr 5. doi: 10.1111/bph.13810. PMID:28380256 doi:http://dx.doi.org/10.1111/bph.13810
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