6c57: Difference between revisions
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==Crystal structure of mutant human geranylgeranyl pyrophosphate synthase (Y246D) in complex with bisphosphonate inhibitor FV0109== | |||
<StructureSection load='6c57' size='340' side='right'caption='[[6c57]], [[Resolution|resolution]] 3.50Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6c57]] is a 2 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=6C57 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6C57 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]] 3.5Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FV9:{[(2-{3-[(4-fluorobenzene-1-carbonyl)amino]phenyl}thieno[2,3-d]pyrimidin-4-yl)amino]methylene}bis(phosphonic+acid)'>FV9</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=6c57 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6c57 OCA], [https://pdbe.org/6c57 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6c57 RCSB], [https://www.ebi.ac.uk/pdbsum/6c57 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6c57 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/GGPPS_HUMAN GGPPS_HUMAN] Catalyzes the trans-addition of the three molecules of IPP onto DMAPP to form geranylgeranyl pyrophosphate, an important precursor of carotenoids and geranylated proteins. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Post-translational prenylation of the small GTP-binding proteins (GTPases) is vital to a plethora of biological processes, including cellular proliferation. We have identified a new class of thienopyrimidine-based bisphosphonate (ThP-BP) inhibitors of the human geranylgeranyl pyrophosphate synthase (hGGPPS) that block protein prenylation in multiple myeloma (MM) cells leading to cellular apoptosis. These inhibitors are also effective in blocking the proliferation of other types of cancer cells. We confirmed intracellular target engagement, demonstrated the mechanism of action leading to apoptosis, and determined a direct correlation between apoptosis and intracellular inhibition of hGGPPS. Administration of a ThP-BP inhibitor to a MM mouse model confirmed in vivo downregulation of Rap1A geranylgeranylation and reduction of monoclonal immunoglobulins (M-protein, a biomarker of disease burden) in the serum. These results provide the first proof-of-principle that hGGPPS is a valuable therapeutic target in oncology and more specifically for the treatment of multiple myeloma. | |||
Unraveling the Prenylation-Cancer Paradox in Multiple Myeloma with Novel Geranylgeranyl Pyrophosphate Synthase (GGPPS) Inhibitors.,Lacbay CM, Waller DD, Park J, Gomez Palou M, Vincent F, Huang XF, Ta V, Berghuis AM, Sebag M, Tsantrizos YS J Med Chem. 2018 Aug 9;61(15):6904-6917. doi: 10.1021/acs.jmedchem.8b00886. Epub , 2018 Jul 25. PMID:30016091<ref>PMID:30016091</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6c57" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Geranylgeranyl pyrophosphate synthase 3D structures|Geranylgeranyl pyrophosphate synthase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Berghuis AM]] | |||
[[Category: Bin X]] | |||
[[Category: Park J]] | |||
[[Category: Tsantrizos YS]] | |||
[[Category: Vincent F]] | |||
Latest revision as of 17:56, 4 October 2023
Crystal structure of mutant human geranylgeranyl pyrophosphate synthase (Y246D) in complex with bisphosphonate inhibitor FV0109Crystal structure of mutant human geranylgeranyl pyrophosphate synthase (Y246D) in complex with bisphosphonate inhibitor FV0109
Structural highlights
FunctionGGPPS_HUMAN Catalyzes the trans-addition of the three molecules of IPP onto DMAPP to form geranylgeranyl pyrophosphate, an important precursor of carotenoids and geranylated proteins. Publication Abstract from PubMedPost-translational prenylation of the small GTP-binding proteins (GTPases) is vital to a plethora of biological processes, including cellular proliferation. We have identified a new class of thienopyrimidine-based bisphosphonate (ThP-BP) inhibitors of the human geranylgeranyl pyrophosphate synthase (hGGPPS) that block protein prenylation in multiple myeloma (MM) cells leading to cellular apoptosis. These inhibitors are also effective in blocking the proliferation of other types of cancer cells. We confirmed intracellular target engagement, demonstrated the mechanism of action leading to apoptosis, and determined a direct correlation between apoptosis and intracellular inhibition of hGGPPS. Administration of a ThP-BP inhibitor to a MM mouse model confirmed in vivo downregulation of Rap1A geranylgeranylation and reduction of monoclonal immunoglobulins (M-protein, a biomarker of disease burden) in the serum. These results provide the first proof-of-principle that hGGPPS is a valuable therapeutic target in oncology and more specifically for the treatment of multiple myeloma. Unraveling the Prenylation-Cancer Paradox in Multiple Myeloma with Novel Geranylgeranyl Pyrophosphate Synthase (GGPPS) Inhibitors.,Lacbay CM, Waller DD, Park J, Gomez Palou M, Vincent F, Huang XF, Ta V, Berghuis AM, Sebag M, Tsantrizos YS J Med Chem. 2018 Aug 9;61(15):6904-6917. doi: 10.1021/acs.jmedchem.8b00886. Epub , 2018 Jul 25. PMID:30016091[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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