4lpg: Difference between revisions
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==Crystal structure of human FPPS in complex with CL01131== | |||
<StructureSection load='4lpg' size='340' side='right'caption='[[4lpg]], [[Resolution|resolution]] 2.35Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4lpg]] 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=4LPG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4LPG FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.35Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1MV:({[6-(4-METHYLPHENYL)THIENO[2,3-D]PYRIMIDIN-4-YL]AMINO}METHANEDIYL)BIS(PHOSPHONIC+ACID)'>1MV</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></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=4lpg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4lpg OCA], [https://pdbe.org/4lpg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4lpg RCSB], [https://www.ebi.ac.uk/pdbsum/4lpg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4lpg ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[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;"> | |||
== Publication Abstract from PubMed == | |||
Human farnesyl pyrophosphate synthase (hFPPS) is the gate-keeper of mammalian isoprenoids and the key target of bisphosphonate drugs. Bisphosphonates suffer from poor "drug-like" properties and are mainly effective in treating skeletal diseases. Recent investigations have implicated hFPPS in various nonskeletal diseases, including Alzheimer's disease (AD). Analysis of single nucleotide polymorphisms in the hFPPS gene and mRNA levels in autopsy-confirmed AD subjects was undertaken, and a genetic link between hFPPS and phosphorylated tau (P-Tau) levels in the human brain was identified. Elevated P-Tau levels are strongly implicated in AD progression. The development of nonbisphosphonate inhibitors can provide molecular tools for validating hFPPS as a therapeutic target for tauopathy-associated neurodegeneration. A multistage screening protocol led to the identification of a new monophosphonate chemotype that bind in an allosteric pocket of hFPPS. Optimization of these compounds could lead to human therapeutics that block tau metabolism and arrest the progression of neurodegeneration. | |||
Multistage Screening Reveals Chameleon Ligands of the Human Farnesyl Pyrophosphate Synthase: Implications to Drug Discovery for Neurodegenerative Diseases.,De Schutter JW, Park J, Leung CY, Gormley P, Lin YS, Hu Z, Berghuis AM, Poirier J, Tsantrizos YS J Med Chem. 2014 Jun 23. PMID:24911527<ref>PMID:24911527</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4lpg" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Farnesyl diphosphate synthase 3D structures|Farnesyl diphosphate synthase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Berghuis AM]] | |||
[[Category: Leung CY]] | |||
[[Category: Park J]] | |||
[[Category: Tsantrizos YS]] | |||
Latest revision as of 19:23, 20 September 2023
Crystal structure of human FPPS in complex with CL01131Crystal structure of human FPPS in complex with CL01131
Structural highlights
FunctionFPPS_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 PubMedHuman farnesyl pyrophosphate synthase (hFPPS) is the gate-keeper of mammalian isoprenoids and the key target of bisphosphonate drugs. Bisphosphonates suffer from poor "drug-like" properties and are mainly effective in treating skeletal diseases. Recent investigations have implicated hFPPS in various nonskeletal diseases, including Alzheimer's disease (AD). Analysis of single nucleotide polymorphisms in the hFPPS gene and mRNA levels in autopsy-confirmed AD subjects was undertaken, and a genetic link between hFPPS and phosphorylated tau (P-Tau) levels in the human brain was identified. Elevated P-Tau levels are strongly implicated in AD progression. The development of nonbisphosphonate inhibitors can provide molecular tools for validating hFPPS as a therapeutic target for tauopathy-associated neurodegeneration. A multistage screening protocol led to the identification of a new monophosphonate chemotype that bind in an allosteric pocket of hFPPS. Optimization of these compounds could lead to human therapeutics that block tau metabolism and arrest the progression of neurodegeneration. Multistage Screening Reveals Chameleon Ligands of the Human Farnesyl Pyrophosphate Synthase: Implications to Drug Discovery for Neurodegenerative Diseases.,De Schutter JW, Park J, Leung CY, Gormley P, Lin YS, Hu Z, Berghuis AM, Poirier J, Tsantrizos YS J Med Chem. 2014 Jun 23. PMID:24911527[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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