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| | ==Crystal Structure of Mycobacterium Tuberculosis Decaprenyl Diphosphate Synthase in Complex with BPH-640== | | ==Crystal Structure of Mycobacterium Tuberculosis Decaprenyl Diphosphate Synthase in Complex with BPH-640== |
| - | <StructureSection load='4onc' size='340' side='right' caption='[[4onc]], [[Resolution|resolution]] 1.83Å' scene=''> | + | <StructureSection load='4onc' size='340' side='right'caption='[[4onc]], [[Resolution|resolution]] 1.83Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4onc]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_tuberculosis"_(zopf_1883)_klein_1884 "bacillus tuberculosis" (zopf 1883) klein 1884]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ONC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ONC FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4onc]] 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=4ONC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ONC FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=40B:[HYDROXY(1,1 3,1-TERPHENYL-3-YL)METHANEDIYL]BIS(PHOSPHONIC+ACID)'>40B</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]] 1.83Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Rv2361c ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1773 "Bacillus tuberculosis" (Zopf 1883) Klein 1884])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=40B:[HYDROXY(1,1 3,1-TERPHENYL-3-YL)METHANEDIYL]BIS(PHOSPHONIC+ACID)'>40B</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=4onc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4onc OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4onc RCSB], [http://www.ebi.ac.uk/pdbsum/4onc 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=4onc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4onc OCA], [https://pdbe.org/4onc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4onc RCSB], [https://www.ebi.ac.uk/pdbsum/4onc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4onc ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/DPDS_MYCTU DPDS_MYCTU]] Catalyzes the sequential condensation of isopentenyl diphosphate (IPP) in the cis configuration with (2Z,6E)-farnesyl diphosphate (Z-FPP or EZ-FPP) generating the 50 carbon product trans,polycis-decaprenyl diphosphate. When (2E,6E)-farnesyl diphosphate (E-FPP or EE-FPP) is used in vitro, both primary products decaprenyl diphosphate and (2E,6E,10E)-geranylgeranyl diphosphate (EEE-GGPP) are synthesized. M.tuberculosis does not synthesize (2E,6E,10Z)-geranylgeranyl diphosphate (EEZ-GGPP) and heptaprenyl diphosphate. Can also accept many different allylic substrates, including E-geranyl diphosphate (E-GPP), neryl diphosphate (NPP), and all-trans-geranyl-geranyl diphosphate.<ref>PMID:11004176</ref> <ref>PMID:10816587</ref> <ref>PMID:15516568</ref> | + | [https://www.uniprot.org/uniprot/DPDS_MYCTU DPDS_MYCTU] Catalyzes the sequential condensation of isopentenyl diphosphate (IPP) in the cis configuration with (2Z,6E)-farnesyl diphosphate (Z-FPP or EZ-FPP) generating the 50 carbon product trans,polycis-decaprenyl diphosphate. When (2E,6E)-farnesyl diphosphate (E-FPP or EE-FPP) is used in vitro, both primary products decaprenyl diphosphate and (2E,6E,10E)-geranylgeranyl diphosphate (EEE-GGPP) are synthesized. M.tuberculosis does not synthesize (2E,6E,10Z)-geranylgeranyl diphosphate (EEZ-GGPP) and heptaprenyl diphosphate. Can also accept many different allylic substrates, including E-geranyl diphosphate (E-GPP), neryl diphosphate (NPP), and all-trans-geranyl-geranyl diphosphate.<ref>PMID:11004176</ref> <ref>PMID:10816587</ref> <ref>PMID:15516568</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | + | <div class="pdbe-citations 4onc" style="background-color:#fffaf0;"></div> |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Chan, H C]] | + | [[Category: Large Structures]] |
| - | [[Category: Feng, X]] | + | [[Category: Mycobacterium tuberculosis]] |
| - | [[Category: Ko, T P]] | + | [[Category: Chan HC]] |
| - | [[Category: Decaprenyl diphosphate synthase]] | + | [[Category: Feng X]] |
| - | [[Category: Polyprenyl transferase]] | + | [[Category: Ko TP]] |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Function
DPDS_MYCTU Catalyzes the sequential condensation of isopentenyl diphosphate (IPP) in the cis configuration with (2Z,6E)-farnesyl diphosphate (Z-FPP or EZ-FPP) generating the 50 carbon product trans,polycis-decaprenyl diphosphate. When (2E,6E)-farnesyl diphosphate (E-FPP or EE-FPP) is used in vitro, both primary products decaprenyl diphosphate and (2E,6E,10E)-geranylgeranyl diphosphate (EEE-GGPP) are synthesized. M.tuberculosis does not synthesize (2E,6E,10Z)-geranylgeranyl diphosphate (EEZ-GGPP) and heptaprenyl diphosphate. Can also accept many different allylic substrates, including E-geranyl diphosphate (E-GPP), neryl diphosphate (NPP), and all-trans-geranyl-geranyl diphosphate.[1] [2] [3]
Publication Abstract from PubMed
We have obtained the structure of the bacterial diterpene synthase, tuberculosinol/iso-tuberculosinol synthase (Rv3378c) from Mycobacterium tuberculosis , a target for anti-infective therapies that block virulence factor formation. This phosphatase adopts the same fold as found in the Z- or cis-prenyltransferases. We also obtained structures containing the tuberculosinyl diphosphate substrate together with one bisphosphonate inhibitor-bound structure. These structures together with the results of site-directed mutagenesis suggest an unusual mechanism of action involving two Tyr residues. Given the similarity in local and global structure between Rv3378c and the M. tuberculosis cis-decaprenyl diphosphate synthase (DPPS; Rv2361c), the possibility exists for the development of inhibitors that target not only virulence but also cell wall biosynthesis, based in part on the structures reported here.
Structure and Inhibition of Tuberculosinol Synthase and Decaprenyl Diphosphate Synthase from Mycobacterium tuberculosis.,Chan HC, Feng X, Ko TP, Huang CH, Hu Y, Zheng Y, Bogue S, Nakano C, Hoshino T, Zhang L, Lv P, Liu W, Crick DC, Liang PH, Wang AH, Oldfield E, Guo RT J Am Chem Soc. 2014 Feb 5. PMID:24475925[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Crick DC, Schulbach MC, Zink EE, Macchia M, Barontini S, Besra GS, Brennan PJ. Polyprenyl phosphate biosynthesis in Mycobacterium tuberculosis and Mycobacterium smegmatis. J Bacteriol. 2000 Oct;182(20):5771-8. PMID:11004176
- ↑ Schulbach MC, Brennan PJ, Crick DC. Identification of a short (C15) chain Z-isoprenyl diphosphate synthase and a homologous long (C50) chain isoprenyl diphosphate synthase in Mycobacterium tuberculosis. J Biol Chem. 2000 Jul 28;275(30):22876-81. PMID:10816587 doi:http://dx.doi.org/10.1074/jbc.M003194200
- ↑ Kaur D, Brennan PJ, Crick DC. Decaprenyl diphosphate synthesis in Mycobacterium tuberculosis. J Bacteriol. 2004 Nov;186(22):7564-70. PMID:15516568 doi:http://dx.doi.org/10.1128/JB.186.22.7564-7570.2004
- ↑ Chan HC, Feng X, Ko TP, Huang CH, Hu Y, Zheng Y, Bogue S, Nakano C, Hoshino T, Zhang L, Lv P, Liu W, Crick DC, Liang PH, Wang AH, Oldfield E, Guo RT. Structure and Inhibition of Tuberculosinol Synthase and Decaprenyl Diphosphate Synthase from Mycobacterium tuberculosis. J Am Chem Soc. 2014 Feb 5. PMID:24475925 doi:http://dx.doi.org/10.1021/ja413127v
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