3rbm

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Current revision (12:17, 14 March 2024) (edit) (undo)
 
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<StructureSection load='3rbm' size='340' side='right'caption='[[3rbm]], [[Resolution|resolution]] 2.61&Aring;' scene=''>
<StructureSection load='3rbm' size='340' side='right'caption='[[3rbm]], [[Resolution|resolution]] 2.61&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[3rbm]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Plavs Plavs]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3RBM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3RBM FirstGlance]. <br>
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<table><tr><td colspan='2'>[[3rbm]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_vivax_Sal-1 Plasmodium vivax Sal-1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3RBM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3RBM FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=B73:3-(2,2-DIPHOSPHONOETHYL)-1-DODECYL-1H-IMIDAZOL-3-IUM'>B73</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.61&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3ryw|3ryw]]</div></td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=B73:3-(2,2-DIPHOSPHONOETHYL)-1-DODECYL-1H-IMIDAZOL-3-IUM'>B73</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PVX_092040 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=126793 PLAVS])</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3rbm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3rbm OCA], [https://pdbe.org/3rbm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3rbm RCSB], [https://www.ebi.ac.uk/pdbsum/3rbm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3rbm ProSAT]</span></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=3rbm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3rbm OCA], [https://pdbe.org/3rbm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3rbm RCSB], [https://www.ebi.ac.uk/pdbsum/3rbm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3rbm ProSAT]</span></td></tr>
</table>
</table>
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<div style="background-color:#fffaf0;">
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== Function ==
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== Publication Abstract from PubMed ==
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[https://www.uniprot.org/uniprot/A5K4U6_PLAVS A5K4U6_PLAVS]
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We report the results of an in vitro screening assay targeting the intraerythrocytic form of the malaria parasite Plasmodium falciparum using a library of 560 prenyl-synthase inhibitors. Based on "growth-rescue" and enzyme-inhibition experiments, geranylgeranyl diphosphate synthase (GGPPS) is shown to be a major target for the most potent leads, BPH-703 and BPH-811, lipophilic analogs of the bone-resorption drugs zoledronate and risedronate. We determined the crystal structures of these inhibitors bound to a Plasmodium GGPPS finding that their head groups bind to the [Mg(2+)](3) cluster in the active site in a similar manner to that found with their more hydrophilic parents, whereas their hydrophobic tails occupy a long-hydrophobic tunnel spanning both molecules in the dimer. The results of isothermal-titration-calorimetric experiments show that both lipophilic bisphosphonates bind to GGPPS with, on average, a DeltaG of -9 kcal mol(-1), only 0.5 kcal mol(-1) worse than the parent bisphosphonates, consistent with the observation that conversion to the lipophilic species has only a minor effect on enzyme activity. However, only the lipophilic species are active in cells. We also tested both compounds in mice, finding major decreases in parasitemia and 100% survival. These results are of broad general interest because they indicate that it may be possible to overcome barriers to cell penetration of existing bisphosphonate drugs in this and other systems by simple covalent modification to form lipophilic analogs that retain their enzyme-inhibition activity and are also effective in vitro and in vivo.
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Lipophilic analogs of zoledronate and risedronate inhibit Plasmodium geranylgeranyl diphosphate synthase (GGPPS) and exhibit potent antimalarial activity.,No JH, de Macedo Dossin F, Zhang Y, Liu YL, Zhu W, Feng X, Yoo JA, Lee E, Wang K, Hui R, Freitas-Junior LH, Oldfield E Proc Natl Acad Sci U S A. 2012 Mar 13;109(11):4058-63. Epub 2012 Mar 5. PMID:22392982<ref>PMID:22392982</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 3rbm" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Plavs]]
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[[Category: Plasmodium vivax Sal-1]]
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[[Category: Liu, Y L]]
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[[Category: Liu YL]]
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[[Category: No, J H]]
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[[Category: No JH]]
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[[Category: Oldfield, E]]
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[[Category: Oldfield E]]
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[[Category: Alpha-helice]]
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[[Category: Isoprene biosynthesis]]
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[[Category: Transferase-transferase inhibitor complex]]
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Current revision

Crystal structure of Plasmodium vivax geranylgeranylpyrophosphate synthase complexed with BPH -703

PDB ID 3rbm

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OCA

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