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7rni
From Proteopedia
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| - | ==== | + | ==Discovery of an Anion-Dependent Farnesyltransferase Inhibitor from a Phenotypic Screen== |
| - | <StructureSection load='7rni' size='340' side='right'caption='[[7rni]]' scene=''> | + | <StructureSection load='7rni' size='340' side='right'caption='[[7rni]], [[Resolution|resolution]] 1.98Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7rni]] 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=7RNI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7RNI FirstGlance]. <br> |
| - | </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=7rni FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7rni OCA], [https://pdbe.org/7rni PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7rni RCSB], [https://www.ebi.ac.uk/pdbsum/7rni PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7rni ProSAT]</span></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.978Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=60I:[4-[[3-(2,2-dimethylpropyl)-1~{H}-benzimidazol-2-yl]methyl]piperazin-1-yl]-(1,3,5-trimethylpyrazol-4-yl)methanone'>60I</scene>, <scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=DMA:DIMETHYLALLYL+DIPHOSPHATE'>DMA</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=7rni FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7rni OCA], [https://pdbe.org/7rni PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7rni RCSB], [https://www.ebi.ac.uk/pdbsum/7rni PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7rni ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Function == | ||
| + | [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;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | By employing a phenotypic screen, a set of compounds, exemplified by 1, were identified which potentiate the ability of histone deacetylase inhibitor vorinostat to reverse HIV latency. Proteome enrichment followed by quantitative mass spectrometric analysis employing a modified analogue of 1 as affinity bait identified farnesyl transferase (FTase) as the primary interacting protein in cell lysates. This ligand-FTase binding interaction was confirmed via X-ray crystallography and temperature dependent fluorescence studies, despite 1 lacking structural and binding similarity to known FTase inhibitors. Although multiple lines of evidence established the binding interaction, these ligands exhibited minimal inhibitory activity in a cell-free biochemical FTase inhibition assay. Subsequent modification of the biochemical assay by increasing anion concentration demonstrated FTase inhibitory activity in this novel class. We propose 1 binds together with the anion in the active site to inhibit farnesyl transferase. Implications for phenotypic screening deconvolution and HIV reactivation are discussed. | ||
| + | |||
| + | Discovery of an Anion-Dependent Farnesyltransferase Inhibitor from a Phenotypic Screen.,Bukhtiyarova M, Cook EM, Hancock PJ, Hruza AW, Shaw AW, Adam GC, Barnard RJO, McKenna PM, Holloway MK, Bell IM, Carroll S, Cornella-Taracido I, Cox CD, Kutchukian PS, Powell DA, Strickland C, Trotter BW, Tudor M, Wolkenberg S, Li J, Tellers DM ACS Med Chem Lett. 2020 Dec 23;12(1):99-106. doi: 10.1021/acsmedchemlett.0c00551. , eCollection 2021 Jan 14. PMID:33488970<ref>PMID:33488970</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7rni" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: | + | [[Category: Rattus norvegicus]] |
| + | [[Category: Hruza A]] | ||
| + | [[Category: Strickland CL]] | ||
Current revision
Discovery of an Anion-Dependent Farnesyltransferase Inhibitor from a Phenotypic Screen
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