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| | <StructureSection load='4n1z' size='340' side='right'caption='[[4n1z]], [[Resolution|resolution]] 2.35Å' scene=''> | | <StructureSection load='4n1z' size='340' side='right'caption='[[4n1z]], [[Resolution|resolution]] 2.35Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4n1z]] 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=4N1Z OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4N1Z FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4n1z]] 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=4N1Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4N1Z FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=N1Z:HYDROGEN+[(1S)-1-HYDROXY-2-(3-OCTYL-1H-IMIDAZOL-3-IUM-1-YL)-1-PHOSPHONOETHYL]PHOSPHONATE'>N1Z</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=N1Z:HYDROGEN+[(1S)-1-HYDROXY-2-(3-OCTYL-1H-IMIDAZOL-3-IUM-1-YL)-1-PHOSPHONOETHYL]PHOSPHONATE'>N1Z</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4ga3|4ga3]]</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=4n1z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4n1z OCA], [https://pdbe.org/4n1z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4n1z RCSB], [https://www.ebi.ac.uk/pdbsum/4n1z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4n1z ProSAT]</span></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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4n1z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4n1z OCA], [http://pdbe.org/4n1z PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4n1z RCSB], [http://www.ebi.ac.uk/pdbsum/4n1z PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4n1z 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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| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Farnesyl diphosphate synthase|Farnesyl diphosphate synthase]] | + | *[[Farnesyl diphosphate synthase 3D structures|Farnesyl diphosphate synthase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Liu, Y L]] | + | [[Category: Liu YL]] |
| - | [[Category: Oldfield, E]] | + | [[Category: Oldfield E]] |
| - | [[Category: Verma, I]] | + | [[Category: Verma I]] |
| - | [[Category: Xia, Y]] | + | [[Category: Xia Y]] |
| - | [[Category: Zhang, Y]] | + | [[Category: Zhang Y]] |
| - | [[Category: Alpha fold]]
| + | |
| - | [[Category: Cytosol]]
| + | |
| - | [[Category: Dephosphorylation]]
| + | |
| - | [[Category: Ionization]]
| + | |
| - | [[Category: Synthase]]
| + | |
| - | [[Category: Transferase]]
| + | |
| 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
Lung cancer is the most common human malignancy and leads to about one-third of all cancer-related deaths. Lung adenocarcinomas harboring KRAS mutations, in contrast to those with EGFR and EML4-ALK mutations, have not been successfully targeted. We describe a combination therapy for treating these malignancies with two agents: a lipophilic bisphosphonate and rapamycin. This drug combination is much more effective than either agent acting alone in the KRAS G12D-induced mouse lung model. Lipophilic bisphosphonates inhibit both farnesyl and geranylgeranyldiphosphate synthases, effectively blocking prenylation of KRAS and other small G proteins (heterotrimeric GTP-binding protein, heterotrimeric guanine nucleotide-binding proteins) critical for tumor growth and cell survival. Bisphosphonate treatment of cells initiated autophagy but was ultimately unsuccessful and led to p62 accumulation and concomitant nuclear factor kappaB (NF-kappaB) activation, resulting in dampened efficacy in vivo. However, we found that rapamycin, in addition to inhibiting the mammalian target of rapamycin (mTOR) pathway, facilitated autophagy and prevented p62 accumulation-induced NF-kappaB activation and tumor cell proliferation. Overall, these results suggest that using lipophilic bisphosphonates in combination with rapamycin may provide an effective strategy for targeting lung adenocarcinomas harboring KRAS mutations.
A combination therapy for KRAS-driven lung adenocarcinomas using lipophilic bisphosphonates and rapamycin.,Xia Y, Liu YL, Xie Y, Zhu W, Guerra F, Shen S, Yeddula N, Fischer W, Low W, Zhou X, Zhang Y, Oldfield E, Verma IM Sci Transl Med. 2014 Nov 19;6(263):263ra161. doi: 10.1126/scitranslmed.3010382. PMID:25411474[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Xia Y, Liu YL, Xie Y, Zhu W, Guerra F, Shen S, Yeddula N, Fischer W, Low W, Zhou X, Zhang Y, Oldfield E, Verma IM. A combination therapy for KRAS-driven lung adenocarcinomas using lipophilic bisphosphonates and rapamycin. Sci Transl Med. 2014 Nov 19;6(263):263ra161. doi: 10.1126/scitranslmed.3010382. PMID:25411474 doi:http://dx.doi.org/10.1126/scitranslmed.3010382
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