3khp

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of a possible dehydrogenase from Mycobacterium tuberculosis at 2.3A resolution

Structural highlights

3khp is a 4 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 2.3Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

HTDY_MYCTU Shows trans-enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydratase activity (PubMed:17240207). In vitro, can hydrate various enoyl-CoA such as (2E)-hexenoyl-CoA, (2E)-octenoyl-CoA, (2E)-decenoyl-CoA, (2E)-dodecenoyl-CoA and (2E)-hexadecenoyl-CoA (PubMed:17240207, PubMed:19136596). May contribute to the persistence of the tuberculosis infection by inducing COX-2 expression in macrophages through MAPK-NF-kappaB signaling pathway (PubMed:24907510).^[1] ^[2] ^[3]

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

High-resolution three-dimensional structures of essential Mycobacterium tuberculosis (Mtb) proteins provide templates for TB drug design, but are available for only a small fraction of the Mtb proteome. Here we evaluate an intra-genus "homolog-rescue" strategy to increase the structural information available for TB drug discovery by using mycobacterial homologs with conserved active sites. Of 179 potential TB drug targets selected for x-ray structure determination, only 16 yielded a crystal structure. By adding 1675 homologs from nine other mycobacterial species to the pipeline, structures representing an additional 52 otherwise intractable targets were solved. To determine whether these homolog structures would be useful surrogates in TB drug design, we compared the active sites of 106 pairs of Mtb and non-TB mycobacterial (NTM) enzyme homologs with experimentally determined structures, using three metrics of active site similarity, including superposition of continuous pharmacophoric property distributions. Pair-wise structural comparisons revealed that 19/22 pairs with >55% overall sequence identity had active site Calpha RMSD <1 A, >85% side chain identity, and >/=80% PSAPF (similarity based on pharmacophoric properties) indicating highly conserved active site shape and chemistry. Applying these results to the 52 NTM structures described above, 41 shared >55% sequence identity with the Mtb target, thus increasing the effective structural coverage of the 179 Mtb targets over three-fold (from 9% to 32%). The utility of these structures in TB drug design can be tested by designing inhibitors using the homolog structure and assaying the cognate Mtb enzyme; a promising test case, Mtb cytidylate kinase, is described. The homolog-rescue strategy evaluated here for TB is also generalizable to drug targets for other diseases.

Increasing the structural coverage of tuberculosis drug targets.,Baugh L, Phan I, Begley DW, Clifton MC, Armour B, Dranow DM, Taylor BM, Muruthi MM, Abendroth J, Fairman JW, Fox D 3rd, Dieterich SH, Staker BL, Gardberg AS, Choi R, Hewitt SN, Napuli AJ, Myers J, Barrett LK, Zhang Y, Ferrell M, Mundt E, Thompkins K, Tran N, Lyons-Abbott S, Abramov A, Sekar A, Serbzhinskiy D, Lorimer D, Buchko GW, Stacy R, Stewart LJ, Edwards TE, Van Voorhis WC, Myler PJ Tuberculosis (Edinb). 2014 Dec 19. pii: S1472-9792(14)20565-8. doi:, 10.1016/j.tube.2014.12.003. PMID:25613812^[4]

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

References

↑ Sacco E, Legendre V, Laval F, Zerbib D, Montrozier H, Eynard N, Guilhot C, Daffé M, Quémard A. Rv3389C from Mycobacterium tuberculosis, a member of the (R)-specific hydratase/dehydratase family. Biochim Biophys Acta. 2007 Feb;1774(2):303-11. PMID:17240207 doi:10.1016/j.bbapap.2006.11.016
↑ Gurvitz A, Hiltunen JK, Kastaniotis AJ. Heterologous expression of mycobacterial proteins in Saccharomyces cerevisiae reveals two physiologically functional 3-hydroxyacyl-thioester dehydratases, HtdX and HtdY, in addition to HadABC and HtdZ. J Bacteriol. 2009 Apr;191(8):2683-90. doi: 10.1128/JB.01046-08. Epub 2009 Jan 9. PMID:19136596 doi:http://dx.doi.org/10.1128/JB.01046-08
↑ Zhao JW, Sun ZQ, Zhang XY, Zhang Y, Liu J, Ye J, Chen CC, Samten B, Wang HH, Guo XK, Zhang SL. Mycobacterial 3-hydroxyacyl-l-thioester dehydratase Y derived from Mycobacterium tuberculosis induces COX-2 expression in mouse macrophages through MAPK-NF-κB pathway. Immunol Lett. 2014 Sep;161(1):125-32. PMID:24907510 doi:10.1016/j.imlet.2014.05.013
↑ Baugh L, Phan I, Begley DW, Clifton MC, Armour B, Dranow DM, Taylor BM, Muruthi MM, Abendroth J, Fairman JW, Fox D 3rd, Dieterich SH, Staker BL, Gardberg AS, Choi R, Hewitt SN, Napuli AJ, Myers J, Barrett LK, Zhang Y, Ferrell M, Mundt E, Thompkins K, Tran N, Lyons-Abbott S, Abramov A, Sekar A, Serbzhinskiy D, Lorimer D, Buchko GW, Stacy R, Stewart LJ, Edwards TE, Van Voorhis WC, Myler PJ. Increasing the structural coverage of tuberculosis drug targets. Tuberculosis (Edinb). 2014 Dec 19. pii: S1472-9792(14)20565-8. doi:, 10.1016/j.tube.2014.12.003. PMID:25613812 doi:http://dx.doi.org/10.1016/j.tube.2014.12.003

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3khp"

Categories: Large Structures | Mycobacterium tuberculosis H37Rv

@@ Line 1: / Line 1: @@
 ==Crystal structure of a possible dehydrogenase from Mycobacterium tuberculosis at 2.3A resolution==
-<StructureSection load='3khp' size='340' side='right' caption='[[3khp]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
+<StructureSection load='3khp' size='340' side='right'caption='[[3khp]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3khp]] is a 4 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=3KHP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3KHP FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3khp]] is a 4 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=3KHP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3KHP FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=TLA:L(+)-TARTARIC+ACID'>TLA</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]] 2.3&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MT3496, Rv3389c ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83332 MYCTU])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=TLA:L(+)-TARTARIC+ACID'>TLA</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=3khp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3khp OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3khp RCSB], [http://www.ebi.ac.uk/pdbsum/3khp PDBsum]</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=3khp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3khp OCA], [https://pdbe.org/3khp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3khp RCSB], [https://www.ebi.ac.uk/pdbsum/3khp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3khp ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/HTDY_MYCTU HTDY_MYCTU] Shows trans-enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydratase activity (PubMed:17240207). In vitro, can hydrate various enoyl-CoA such as (2E)-hexenoyl-CoA, (2E)-octenoyl-CoA, (2E)-decenoyl-CoA, (2E)-dodecenoyl-CoA and (2E)-hexadecenoyl-CoA (PubMed:17240207, PubMed:19136596). May contribute to the persistence of the tuberculosis infection by inducing COX-2 expression in macrophages through MAPK-NF-kappaB signaling pathway (PubMed:24907510).<ref>PMID:17240207</ref> <ref>PMID:19136596</ref> <ref>PMID:24907510</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/kh/3khp_consurf.spt"</scriptWhenChecked>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/kh/3khp_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=3khp ConSurf].
 <div style="clear:both"></div>
 <div style="background-color:#fffaf0;">
@@ Line 25: / Line 28: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 3khp" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Myctu]]
+[[Category: Large Structures]]
-[[Category: Structural genomic]]
+[[Category: Mycobacterium tuberculosis H37Rv]]
-[[Category: Dehydrogenase]]
-[[Category: Mycobacterium tuberculosis]]
-[[Category: Oxidoreductase]]
-[[Category: Ssgcid]]

3khp

From Proteopedia

Current revision

Crystal structure of a possible dehydrogenase from Mycobacterium tuberculosis at 2.3A resolution

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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