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| | ==Aquifex aeolicus IspE in complex with ligand== | | ==Aquifex aeolicus IspE in complex with ligand== |
| - | <StructureSection load='2vf3' size='340' side='right' caption='[[2vf3]], [[Resolution|resolution]] 2.20Å' scene=''> | + | <StructureSection load='2vf3' size='340' side='right'caption='[[2vf3]], [[Resolution|resolution]] 2.20Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2vf3]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/"aquifex_aeolicus"_huber_and_stetter_2001 "aquifex aeolicus" huber and stetter 2001]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VF3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2VF3 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2vf3]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Aquifex_aeolicus Aquifex aeolicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VF3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2VF3 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BR:BROMIDE+ION'>BR</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GVS:ETHYL+{3-[4-AMINO-5-{3-[(CYCLOPROPYLSULFONYL)AMINO]PROP-1-YN-1-YL}-2-OXOPYRIMIDIN-1(2H)-YL]OXETAN-3-YL}ACETATE'>GVS</scene>, <scene name='pdbligand=POP:PYROPHOSPHATE+2-'>POP</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]] 2.2Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2v2v|2v2v]], [[2v2q|2v2q]], [[2v2y|2v2y]], [[2v2z|2v2z]], [[2v34|2v34]], [[2v8p|2v8p]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BR:BROMIDE+ION'>BR</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GVS:ETHYL+{3-[4-AMINO-5-{3-[(CYCLOPROPYLSULFONYL)AMINO]PROP-1-YN-1-YL}-2-OXOPYRIMIDIN-1(2H)-YL]OXETAN-3-YL}ACETATE'>GVS</scene>, <scene name='pdbligand=POP:PYROPHOSPHATE+2-'>POP</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/4-(cytidine_5'-diphospho)-2-C-methyl-D-erythritol_kinase 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.148 2.7.1.148] </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=2vf3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2vf3 OCA], [https://pdbe.org/2vf3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2vf3 RCSB], [https://www.ebi.ac.uk/pdbsum/2vf3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2vf3 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=2vf3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2vf3 OCA], [http://pdbe.org/2vf3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2vf3 RCSB], [http://www.ebi.ac.uk/pdbsum/2vf3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2vf3 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/ISPE_AQUAE ISPE_AQUAE] Catalyzes the phosphorylation of the position 2 hydroxy group of 4-diphosphocytidyl-2C-methyl-D-erythritol.[HAMAP-Rule:MF_00061] |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Aquifex aeolicus huber and stetter 2001]] | + | [[Category: Aquifex aeolicus]] |
| - | [[Category: Alphey, M S]] | + | [[Category: Large Structures]] |
| - | [[Category: Hunter, W N]] | + | [[Category: Alphey MS]] |
| - | [[Category: Aquifex]] | + | [[Category: Hunter WN]] |
| - | [[Category: Atp-binding]]
| + | |
| - | [[Category: Isoprene biosynthesis]]
| + | |
| - | [[Category: Ispe]]
| + | |
| - | [[Category: Kinase]]
| + | |
| - | [[Category: Non-mevalonate]]
| + | |
| - | [[Category: Nucleotide-binding]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Function
ISPE_AQUAE Catalyzes the phosphorylation of the position 2 hydroxy group of 4-diphosphocytidyl-2C-methyl-D-erythritol.[HAMAP-Rule:MF_00061]
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
Enzymes of the non-mevalonate pathway for isoprenoid biosynthesis are therapeutic targets for the treatment of important infectious diseases. Whereas this pathway is absent in humans, it is used by plants, many eubacteria and apicomplexan protozoa, including major human pathogens such as Plasmodium falciparum and Mycobacterium tuberculosis. Herein, we report on the design, preparation and biological evaluation of a new series of ligands for IspE protein, a kinase from this pathway. These inhibitors were developed for the inhibition of IspE from Escherichia coli, using structure-based design approaches. Structure-activity relationships (SARs) and a co-crystal structure of Aquifex aeolicus IspE bound to a representative inhibitor validate the proposed binding mode. The crystal structure shows that the ligand binds in the substrate-rather than the adenosine 5'-triphosphate (ATP)-binding pocket. As predicted, a cyclopropyl substituent occupies a small cavity not used by the substrate. The optimal volume occupancy of this cavity is explored in detail. In the co-crystal structure, a diphosphate anion binds to the Gly-rich loop, which normally accepts the triphosphate moiety of ATP. This structure provides useful insights for future structure-based developments of inhibitors for the parasite enzymes.
Inhibitors of the kinase IspE: structure-activity relationships and co-crystal structure analysis.,Hirsch AK, Alphey MS, Lauw S, Seet M, Barandun L, Eisenreich W, Rohdich F, Hunter WN, Bacher A, Diederich F Org Biomol Chem. 2008 Aug 7;6(15):2719-30. Epub 2008 Jun 2. PMID:18633530[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Hirsch AK, Alphey MS, Lauw S, Seet M, Barandun L, Eisenreich W, Rohdich F, Hunter WN, Bacher A, Diederich F. Inhibitors of the kinase IspE: structure-activity relationships and co-crystal structure analysis. Org Biomol Chem. 2008 Aug 7;6(15):2719-30. Epub 2008 Jun 2. PMID:18633530 doi:http://dx.doi.org/10.1039/b804375b
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