6c56: Difference between revisions
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==Crystal structure of mutant human geranylgeranyl pyrophosphate synthase (Y246D) in its Apo form== | ==Crystal structure of mutant human geranylgeranyl pyrophosphate synthase (Y246D) in its Apo form== | ||
<StructureSection load='6c56' size='340' side='right' caption='[[6c56]], [[Resolution|resolution]] 2.80Å' scene=''> | <StructureSection load='6c56' size='340' side='right'caption='[[6c56]], [[Resolution|resolution]] 2.80Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6c56]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6C56 OCA]. For a <b>guided tour on the structure components</b> use [http:// | <table><tr><td colspan='2'>[[6c56]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6C56 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6C56 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=VT0:{[(2-phenylthieno[2,3-d]pyrimidin-4-yl)amino]methylene}bis(phosphonic+acid)'>VT0</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=VT0:{[(2-phenylthieno[2,3-d]pyrimidin-4-yl)amino]methylene}bis(phosphonic+acid)'>VT0</scene></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http:// | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6c56 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6c56 OCA], [http://pdbe.org/6c56 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6c56 RCSB], [http://www.ebi.ac.uk/pdbsum/6c56 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6c56 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
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</div> | </div> | ||
<div class="pdbe-citations 6c56" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 6c56" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Geranylgeranyl pyrophosphate synthase 3D structures|Geranylgeranyl pyrophosphate synthase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | |||
[[Category: Berghuis, A M]] | [[Category: Berghuis, A M]] | ||
[[Category: Park, J]] | [[Category: Park, J]] | ||
Revision as of 11:53, 11 November 2020
Crystal structure of mutant human geranylgeranyl pyrophosphate synthase (Y246D) in its Apo formCrystal structure of mutant human geranylgeranyl pyrophosphate synthase (Y246D) in its Apo form
Structural highlights
Function[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. 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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