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5jzb

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Crystal structure of HsaD bound to 3,5-dichlorobenzene sulphonamide

Structural highlights

5jzb is a 2 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 2.102Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5jzb"

@@ Line 1: / Line 1: @@
 ==Crystal structure of HsaD bound to 3,5-dichlorobenzene sulphonamide==
-<StructureSection load='5jzb' size='340' side='right' caption='[[5jzb]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
+<StructureSection load='5jzb' size='340' side='right'caption='[[5jzb]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5jzb]] is a 2 chain structure. 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]] 2.102&#8491;</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='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>
+<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>
 </table>
 == 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;">
 == Publication Abstract from PubMed ==
@@ Line 23: / Line 23: @@
 __TOC__
 </StructureSection>
-[[Category: Abihammad, A]]
+[[Category: Large Structures]]
-[[Category: Ballet, R]]
+[[Category: Mycobacterium tuberculosis H37Rv]]
-[[Category: Bhakta, S]]
+[[Category: Abihammad A]]
-[[Category: Ciulli, A]]
+[[Category: Ballet R]]
-[[Category: Eleftheriadou, O]]
+[[Category: Bhakta S]]
-[[Category: Evangelopoulos, D]]
+[[Category: Ciulli A]]
-[[Category: Halman, A]]
+[[Category: Eleftheriadou O]]
-[[Category: Keany, S]]
+[[Category: Evangelopoulos D]]
-[[Category: Lack, N A]]
+[[Category: Halman A]]
-[[Category: Lowe, E]]
+[[Category: Keany S]]
-[[Category: McHugh, T D]]
+[[Category: Lack NA]]
-[[Category: Polycarpou, E]]
+[[Category: Lowe E]]
-[[Category: Ryan, A]]
+[[Category: McHugh TD]]
-[[Category: Sieg, C]]
+[[Category: Polycarpou E]]
-[[Category: Sim, E]]
+[[Category: Ryan A]]
-[[Category: Sinclair, A]]
+[[Category: Sieg C]]
-[[Category: Cholesterol]]
+[[Category: Sim E]]
-[[Category: Hsad]]
+[[Category: Sinclair A]]
-[[Category: Hydrolase]]
-[[Category: Inhibitor]]
-[[Category: M. tuberculosis]]
-[[Category: Mcp-hydrolase]]

5jzb

From Proteopedia

Current revision

Crystal structure of HsaD bound to 3,5-dichlorobenzene sulphonamide

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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