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| | ==Engineered RabGGTase in complex with BMS analogue 16== | | ==Engineered RabGGTase in complex with BMS analogue 16== |
| - | <StructureSection load='4gts' size='340' side='right' caption='[[4gts]], [[Resolution|resolution]] 2.45Å' scene=''> | + | <StructureSection load='4gts' size='340' side='right'caption='[[4gts]], [[Resolution|resolution]] 2.45Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4gts]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Buffalo_rat Buffalo rat]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GTS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4GTS FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4gts]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GTS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4GTS FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7TP:5-{(3R)-3-(4-HYDROXYBENZYL)-4-[(4-METHOXYPHENYL)SULFONYL]-1-[(1-METHYL-1H-IMIDAZOL-5-YL)METHYL]-2,3,4,5-TETRAHYDRO-1H-1,4-BENZODIAZEPIN-7-YL}FURAN-2-CARBALDEHYDE'>7TP</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7TP:5-{(3R)-3-(4-HYDROXYBENZYL)-4-[(4-METHOXYPHENYL)SULFONYL]-1-[(1-METHYL-1H-IMIDAZOL-5-YL)METHYL]-2,3,4,5-TETRAHYDRO-1H-1,4-BENZODIAZEPIN-7-YL}FURAN-2-CARBALDEHYDE'>7TP</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4gtm|4gtm]], [[4gto|4gto]], [[4gtp|4gtp]], [[4gtq|4gtq]], [[4gtr|4gtr]], [[4gtt|4gtt]], [[4gtv|4gtv]]</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=4gts FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gts OCA], [https://pdbe.org/4gts PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4gts RCSB], [https://www.ebi.ac.uk/pdbsum/4gts PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4gts ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Rabggta, Ggta ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Buffalo rat]), Rabggtb, Ggtb ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Buffalo rat])</td></tr>
| + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Protein_geranylgeranyltransferase_type_II Protein geranylgeranyltransferase type II], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.5.1.60 2.5.1.60] </span></td></tr>
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| - | <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=4gts FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gts OCA], [http://pdbe.org/4gts PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4gts RCSB], [http://www.ebi.ac.uk/pdbsum/4gts PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4gts ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PGTA_RAT PGTA_RAT]] Catalyzes the transfer of a geranyl-geranyl moiety from geranyl-geranyl pyrophosphate to both cysteines in Rab proteins with an -XXCC, -XCXC and -CCXX C-terminal, such as RAB1A, RAB3A and RAB5A respectively. [[http://www.uniprot.org/uniprot/PGTB2_RAT PGTB2_RAT]] Catalyzes the transfer of a geranyl-geranyl moiety from geranyl-geranyl pyrophosphate to both cysteines in Rab proteins with an -XXCC, -XCXC and -CCXX C-terminal, such as RAB1A, RAB3A and RAB5A respectively. | + | [https://www.uniprot.org/uniprot/PGTA_RAT PGTA_RAT] Catalyzes the transfer of a geranyl-geranyl moiety from geranyl-geranyl pyrophosphate to both cysteines in Rab proteins with an -XXCC, -XCXC and -CCXX C-terminal, such as RAB1A, RAB3A and RAB5A respectively. |
| | <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== |
| - | *[[Geranylgeranyl transferase|Geranylgeranyl transferase]] | + | *[[Geranylgeranyl transferase 3D structures|Geranylgeranyl transferase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Buffalo rat]] | + | [[Category: Large Structures]] |
| - | [[Category: Protein geranylgeranyltransferase type II]] | + | [[Category: Rattus norvegicus]] |
| - | [[Category: Blankenfeldt, W]] | + | [[Category: Blankenfeldt W]] |
| - | [[Category: Bon, R S]] | + | [[Category: Bon RS]] |
| - | [[Category: Goody, R S]] | + | [[Category: Goody RS]] |
| - | [[Category: Guo, Z]] | + | [[Category: Guo Z]] |
| - | [[Category: Stigter, E A]] | + | [[Category: Stigter EA]] |
| - | [[Category: Waldmann, H]] | + | [[Category: Waldmann H]] |
| - | [[Category: Inhibitor]]
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| - | [[Category: Protein prenylation]]
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| - | [[Category: Transferase-transferase inhibitor complex]]
| + | |
| Structural highlights
Function
PGTA_RAT Catalyzes the transfer of a geranyl-geranyl moiety from geranyl-geranyl pyrophosphate to both cysteines in Rab proteins with an -XXCC, -XCXC and -CCXX C-terminal, such as RAB1A, RAB3A and RAB5A respectively.
Publication Abstract from PubMed
Members of the Ras superfamily of small GTPases are frequently mutated in cancer. Therefore, inhibitors have been developed to address the acitivity of these GTPases by inhibiting their prenylating enzymes FTase, GGTase I, and RabGGTase. In contrast to FTase and GGTase I, only a handful of RabGGTase inhibitors have been developed. The most active RabGGTase inhibitor known until recently was an FTase inhibitor which hit RabGGTase as an off-target. We recently reported our efforts to tune the selectivity of these inhibitors toward RabGGTase. Here we describe an extended set of selective inhibitors. The requirements for selective RabGGTase inhibitors are described in detail, guided by multiple crystal structures. In order to relate in vitro and cellular activity, a high-throughput assay system to detect the attachment of [(3)H]geranylgeranyl groups to Rab was used. Selective RabGGTase inhibition allows the establishment of novel drug discovery programs aimed at the development of anticancer therapeutics.
Development of Selective, Potent RabGGTase Inhibitors.,Stigter EA, Guo Z, Bon RS, Wu YW, Choidas A, Wolf A, Menninger S, Waldmann H, Blankenfeldt W, Goody RS J Med Chem. 2012 Oct 11;55(19):8330-40. doi: 10.1021/jm300624s. Epub 2012 Oct 3. PMID:22963166[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Stigter EA, Guo Z, Bon RS, Wu YW, Choidas A, Wolf A, Menninger S, Waldmann H, Blankenfeldt W, Goody RS. Development of Selective, Potent RabGGTase Inhibitors. J Med Chem. 2012 Oct 11;55(19):8330-40. doi: 10.1021/jm300624s. Epub 2012 Oct 3. PMID:22963166 doi:http://dx.doi.org/10.1021/jm300624s
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