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| | ==Crystal structure of 2C-methyl-D-erythritol 2,4-clycodiphosphate synthase complexed with ligand== | | ==Crystal structure of 2C-methyl-D-erythritol 2,4-clycodiphosphate synthase complexed with ligand== |
| - | <StructureSection load='3fba' size='340' side='right' caption='[[3fba]], [[Resolution|resolution]] 3.10Å' scene=''> | + | <StructureSection load='3fba' size='340' side='right'caption='[[3fba]], [[Resolution|resolution]] 3.10Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3fba]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Ecoli Ecoli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3FBA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3FBA FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3fba]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Ecoli Ecoli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3FBA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3FBA FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=C6B:[(2S,3S,4R,5S)-5-(4-AMINO-2-OXO-PYRIMIDIN-1-YL)-4-HYDROXY-2-(HYDROXYMETHYL)OXOLAN-3-YL]+DIHYDROGEN+PHOSPHATE'>C6B</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=GPP:GERANYL+DIPHOSPHATE'>GPP</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C6B:[(2S,3S,4R,5S)-5-(4-AMINO-2-OXO-PYRIMIDIN-1-YL)-4-HYDROXY-2-(HYDROXYMETHYL)OXOLAN-3-YL]+DIHYDROGEN+PHOSPHATE'>C6B</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=GPP:GERANYL+DIPHOSPHATE'>GPP</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ispF ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83333 ECOLI])</td></tr> | + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ispF ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83333 ECOLI])</td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/2-C-methyl-D-erythritol_2,4-cyclodiphosphate_synthase 2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.6.1.12 4.6.1.12] </span></td></tr> | + | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/2-C-methyl-D-erythritol_2,4-cyclodiphosphate_synthase 2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.6.1.12 4.6.1.12] </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=3fba FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3fba OCA], [http://pdbe.org/3fba PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3fba RCSB], [http://www.ebi.ac.uk/pdbsum/3fba PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3fba 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=3fba FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3fba OCA], [https://pdbe.org/3fba PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3fba RCSB], [https://www.ebi.ac.uk/pdbsum/3fba PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3fba ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/ISPF_ECOLI ISPF_ECOLI]] Involved in the biosynthesis of isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), two major building blocks of isoprenoid compounds. Catalyzes the conversion of 4-diphosphocytidyl-2-C-methyl-D-erythritol 2-phosphate (CDP-ME2P) to 2-C-methyl-D-erythritol 2,4-cyclodiphosphate (ME-CPP) with a corresponding release of cytidine 5-monophosphate (CMP). Also converts 4-diphosphocytidyl-2-C-methyl-D-erythritol into 2-C-methyl-D-erythritol 3,4-cyclophosphate and CMP.<ref>PMID:10694574</ref> <ref>PMID:22839733</ref> | + | [[https://www.uniprot.org/uniprot/ISPF_ECOLI ISPF_ECOLI]] Involved in the biosynthesis of isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), two major building blocks of isoprenoid compounds. Catalyzes the conversion of 4-diphosphocytidyl-2-C-methyl-D-erythritol 2-phosphate (CDP-ME2P) to 2-C-methyl-D-erythritol 2,4-cyclodiphosphate (ME-CPP) with a corresponding release of cytidine 5-monophosphate (CMP). Also converts 4-diphosphocytidyl-2-C-methyl-D-erythritol into 2-C-methyl-D-erythritol 3,4-cyclophosphate and CMP.<ref>PMID:10694574</ref> <ref>PMID:22839733</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | ==See Also== | | ==See Also== |
| - | *[[MECDP synthase|MECDP synthase]] | + | *[[MECDP synthase 3D structures|MECDP synthase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
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| | [[Category: 2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase]] | | [[Category: 2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase]] |
| | [[Category: Ecoli]] | | [[Category: Ecoli]] |
| | + | [[Category: Large Structures]] |
| | [[Category: Hunter, W N]] | | [[Category: Hunter, W N]] |
| | [[Category: Ramsden, N L]] | | [[Category: Ramsden, N L]] |
| Structural highlights
3fba is a 1 chain structure with sequence from Ecoli. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , |
| Gene: | ispF (ECOLI) |
| Activity: | 2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase, with EC number 4.6.1.12 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[ISPF_ECOLI] Involved in the biosynthesis of isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), two major building blocks of isoprenoid compounds. Catalyzes the conversion of 4-diphosphocytidyl-2-C-methyl-D-erythritol 2-phosphate (CDP-ME2P) to 2-C-methyl-D-erythritol 2,4-cyclodiphosphate (ME-CPP) with a corresponding release of cytidine 5-monophosphate (CMP). Also converts 4-diphosphocytidyl-2-C-methyl-D-erythritol into 2-C-methyl-D-erythritol 3,4-cyclophosphate and CMP.[1] [2]
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
The nonmevalonate route to isoprenoid biosynthesis is essential in Gram-negative bacteria and apicomplexan parasites. The enzymes of this pathway are absent from mammals, contributing to their appeal as chemotherapeutic targets. One enzyme, 2C-methyl-d-erythritol-2,4-cyclodiphosphate synthase (IspF), has been validated as a target by genetic approaches in bacteria. Virtual screening against Escherichia coli IspF (EcIspF) was performed by combining a hierarchical filtering methodology with molecular docking. Docked compounds were inspected and 10 selected for experimental validation. A surface plasmon resonance assay was developed and two weak ligands identified. Crystal structures of EcIspF complexes were determined to support rational ligand development. Cytosine analogues and Zn(2+)-binding moieties were characterized. One of the putative Zn(2+)-binding compounds gave the lowest measured K(D) to date (1.92 +/- 0.18 muM). These data provide a framework for the development of IspF inhibitors to generate lead compounds of therapeutic potential against microbial pathogens.
A structure-based approach to ligand discovery for 2C-methyl-D-erythritol-2,4-cyclodiphosphate synthase: a target for antimicrobial therapy.,Ramsden NL, Buetow L, Dawson A, Kemp LA, Ulaganathan V, Brenk R, Klebe G, Hunter WN J Med Chem. 2009 Apr 23;52(8):2531-42. PMID:19320487[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Herz S, Wungsintaweekul J, Schuhr CA, Hecht S, Luttgen H, Sagner S, Fellermeier M, Eisenreich W, Zenk MH, Bacher A, Rohdich F. Biosynthesis of terpenoids: YgbB protein converts 4-diphosphocytidyl-2C-methyl-D-erythritol 2-phosphate to 2C-methyl-D-erythritol 2,4-cyclodiphosphate. Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2486-90. PMID:10694574 doi:http://dx.doi.org/10.1073/pnas.040554697
- ↑ Bitok JK, Meyers CF. 2C-Methyl-d-erythritol 4-phosphate enhances and sustains cyclodiphosphate synthase IspF activity. ACS Chem Biol. 2012 Oct 19;7(10):1702-10. doi: 10.1021/cb300243w. Epub 2012 Aug, 6. PMID:22839733 doi:http://dx.doi.org/10.1021/cb300243w
- ↑ Ramsden NL, Buetow L, Dawson A, Kemp LA, Ulaganathan V, Brenk R, Klebe G, Hunter WN. A structure-based approach to ligand discovery for 2C-methyl-D-erythritol-2,4-cyclodiphosphate synthase: a target for antimicrobial therapy. J Med Chem. 2009 Apr 23;52(8):2531-42. PMID:19320487 doi:10.1021/jm801475n
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