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| | ==FTase in complex with BMS analogue 12== | | ==FTase in complex with BMS analogue 12== |
| - | <StructureSection load='4gtq' size='340' side='right' caption='[[4gtq]], [[Resolution|resolution]] 2.60Å' scene=''> | + | <StructureSection load='4gtq' size='340' side='right'caption='[[4gtq]], [[Resolution|resolution]] 2.60Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4gtq]] 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=4GTQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4GTQ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4gtq]] 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=4GTQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4GTQ FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7TQ:4-({(3R)-7-CYANO-4-[(4-METHOXYPHENYL)SULFONYL]-1-[(1-METHYL-1H-IMIDAZOL-5-YL)METHYL]-2,3,4,5-TETRAHYDRO-1H-1,4-BENZODIAZEPIN-3-YL}METHYL)PHENYL+BENZYLCARBAMATE'>7TQ</scene>, <scene name='pdbligand=FPP:FARNESYL+DIPHOSPHATE'>FPP</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=7TQ:4-({(3R)-7-CYANO-4-[(4-METHOXYPHENYL)SULFONYL]-1-[(1-METHYL-1H-IMIDAZOL-5-YL)METHYL]-2,3,4,5-TETRAHYDRO-1H-1,4-BENZODIAZEPIN-3-YL}METHYL)PHENYL+BENZYLCARBAMATE'>7TQ</scene>, <scene name='pdbligand=FPP:FARNESYL+DIPHOSPHATE'>FPP</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]], [[4gtr|4gtr]], [[4gts|4gts]], [[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=4gtq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gtq OCA], [https://pdbe.org/4gtq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4gtq RCSB], [https://www.ebi.ac.uk/pdbsum/4gtq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4gtq ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Fnta ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Buffalo rat]), Fntb ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Buffalo rat])</td></tr>
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| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Protein_farnesyltransferase Protein farnesyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.5.1.58 2.5.1.58] </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=4gtq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gtq OCA], [http://pdbe.org/4gtq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4gtq RCSB], [http://www.ebi.ac.uk/pdbsum/4gtq PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4gtq ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/FNTA_RAT FNTA_RAT]] Catalyzes the transfer of a farnesyl or geranyl-geranyl moiety from farnesyl or geranyl-geranyl pyrophosphate to a cysteine at the fourth position from the C-terminus of several proteins having the C-terminal sequence Cys-aliphatic-aliphatic-X. The alpha subunit is thought to participate in a stable complex with the substrate. The beta subunit binds the peptide substrate. Through RAC1 prenylation and activation may positively regulate neuromuscular junction development downstream of MUSK (By similarity). [[http://www.uniprot.org/uniprot/FNTB_RAT FNTB_RAT]] Catalyzes the transfer of a farnesyl moiety from farnesyl pyrophosphate to a cysteine at the fourth position from the C-terminus of several proteins. The beta subunit is responsible for peptide-binding. | + | [https://www.uniprot.org/uniprot/FNTA_RAT FNTA_RAT] Catalyzes the transfer of a farnesyl or geranyl-geranyl moiety from farnesyl or geranyl-geranyl pyrophosphate to a cysteine at the fourth position from the C-terminus of several proteins having the C-terminal sequence Cys-aliphatic-aliphatic-X. The alpha subunit is thought to participate in a stable complex with the substrate. The beta subunit binds the peptide substrate. Through RAC1 prenylation and activation may positively regulate neuromuscular junction development downstream of MUSK (By similarity). |
| | <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== |
| - | *[[Farnesyltransferase|Farnesyltransferase]] | + | *[[Farnesyltransferase 3D structures|Farnesyltransferase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Buffalo rat]] | + | [[Category: Large Structures]] |
| - | [[Category: Protein farnesyltransferase]] | + | [[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]]
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| Structural highlights
Function
FNTA_RAT Catalyzes the transfer of a farnesyl or geranyl-geranyl moiety from farnesyl or geranyl-geranyl pyrophosphate to a cysteine at the fourth position from the C-terminus of several proteins having the C-terminal sequence Cys-aliphatic-aliphatic-X. The alpha subunit is thought to participate in a stable complex with the substrate. The beta subunit binds the peptide substrate. Through RAC1 prenylation and activation may positively regulate neuromuscular junction development downstream of MUSK (By similarity).
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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