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| | <StructureSection load='5juz' size='340' side='right'caption='[[5juz]], [[Resolution|resolution]] 2.40Å' scene=''> | | <StructureSection load='5juz' size='340' side='right'caption='[[5juz]], [[Resolution|resolution]] 2.40Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5juz]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5JUZ OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5JUZ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5juz]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5JUZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5JUZ FirstGlance]. <br> |
| - | </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=YL4:[(R)-(2,3-DIHYDRO-1-BENZOFURAN-5-YL){[6-(4-METHYLPHENYL)THIENO[2,3-D]PYRIMIDIN-4-YL]AMINO}METHYL]PHOSPHONIC+ACID'>YL4</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]] 2.4Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5jv2|5jv2]], [[5jv1|5jv1]], [[5jv0|5jv0]]</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=YL4:[(R)-(2,3-DIHYDRO-1-BENZOFURAN-5-YL){[6-(4-METHYLPHENYL)THIENO[2,3-D]PYRIMIDIN-4-YL]AMINO}METHYL]PHOSPHONIC+ACID'>YL4</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">FDPS, FPS, KIAA1293 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=5juz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5juz OCA], [https://pdbe.org/5juz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5juz RCSB], [https://www.ebi.ac.uk/pdbsum/5juz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5juz ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5juz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5juz OCA], [http://pdbe.org/5juz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5juz RCSB], [http://www.ebi.ac.uk/pdbsum/5juz PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5juz ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/FPPS_HUMAN FPPS_HUMAN]] Key enzyme in isoprenoid biosynthesis which catalyzes the formation of farnesyl diphosphate (FPP), a precursor for several classes of essential metabolites including sterols, dolichols, carotenoids, and ubiquinones. FPP also serves as substrate for protein farnesylation and geranylgeranylation. Catalyzes the sequential condensation of isopentenyl pyrophosphate with the allylic pyrophosphates, dimethylallyl pyrophosphate, and then with the resultant geranylpyrophosphate to the ultimate product farnesyl pyrophosphate. | + | [https://www.uniprot.org/uniprot/FPPS_HUMAN FPPS_HUMAN] Key enzyme in isoprenoid biosynthesis which catalyzes the formation of farnesyl diphosphate (FPP), a precursor for several classes of essential metabolites including sterols, dolichols, carotenoids, and ubiquinones. FPP also serves as substrate for protein farnesylation and geranylgeranylation. Catalyzes the sequential condensation of isopentenyl pyrophosphate with the allylic pyrophosphates, dimethylallyl pyrophosphate, and then with the resultant geranylpyrophosphate to the ultimate product farnesyl pyrophosphate. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Berghuis, A M]] | + | [[Category: Berghuis AM]] |
| - | [[Category: Leung, C Y]] | + | [[Category: Leung CY]] |
| - | [[Category: Magder, A]] | + | [[Category: Magder A]] |
| - | [[Category: Park, J]] | + | [[Category: Park J]] |
| - | [[Category: Tsantrizos, Y S]] | + | [[Category: Tsantrizos YS]] |
| - | [[Category: Transferase]]
| + | |
| - | [[Category: Transferase-transferase inhibitor complex]]
| + | |
| Structural highlights
Function
FPPS_HUMAN Key enzyme in isoprenoid biosynthesis which catalyzes the formation of farnesyl diphosphate (FPP), a precursor for several classes of essential metabolites including sterols, dolichols, carotenoids, and ubiquinones. FPP also serves as substrate for protein farnesylation and geranylgeranylation. Catalyzes the sequential condensation of isopentenyl pyrophosphate with the allylic pyrophosphates, dimethylallyl pyrophosphate, and then with the resultant geranylpyrophosphate to the ultimate product farnesyl pyrophosphate.
Publication Abstract from PubMed
The human farnesyl pyrophosphate synthase (hFPPS), a key regulatory enzyme in the mevalonate pathway, catalyzes the biosynthesis of the C-15 isoprenoid farnesyl pyrophosphate (FPP). FPP plays a crucial role in the post-translational prenylation of small GTPases that perform a plethora of cellular functions. Although hFPPS is a well-established therapeutic target for lytic bone diseases, the currently available bisphosphonate drugs exhibit poor cellular uptake and distribution into nonskeletal tissues. Recent drug discovery efforts have focused primarily on allosteric inhibition of hFPPS and the discovery of non-bisphosphonate drugs for potentially treating nonskeletal diseases. Hit-to-lead optimization of a new series of thienopyrimidine-based monosphosphonates (ThP-MPs) led to the identification of analogs with nanomolar potency in inhibiting hFPPS. Their interactions with the allosteric pocket of the enzyme were characterized by crystallography, and the results provide further insight into the pharmacophore requirements for allosteric inhibition.
Pharmacophore Mapping of Thienopyrimidine-Based Monophosphonate (ThP-MP) Inhibitors of the Human Farnesyl Pyrophosphate Synthase.,Park J, Leung CY, Matralis AN, Lacbay CM, Tsakos M, Fernandez De Troconiz G, Berghuis AM, Tsantrizos YS J Med Chem. 2017 Mar 9;60(5):2119-2134. doi: 10.1021/acs.jmedchem.6b01888. Epub, 2017 Feb 28. PMID:28208018[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Park J, Leung CY, Matralis AN, Lacbay CM, Tsakos M, Fernandez De Troconiz G, Berghuis AM, Tsantrizos YS. Pharmacophore Mapping of Thienopyrimidine-Based Monophosphonate (ThP-MP) Inhibitors of the Human Farnesyl Pyrophosphate Synthase. J Med Chem. 2017 Mar 9;60(5):2119-2134. doi: 10.1021/acs.jmedchem.6b01888. Epub, 2017 Feb 28. PMID:28208018 doi:http://dx.doi.org/10.1021/acs.jmedchem.6b01888
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