7RNI
Discovery of an Anion-Dependent Farnesyltransferase Inhibitor from a Phenotypic Screen
Summary for 7RNI
| Entry DOI | 10.2210/pdb7rni/pdb |
| Descriptor | Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha, Protein farnesyltransferase subunit beta, ACETYL GROUP, ... (8 entities in total) |
| Functional Keywords | protein inhibitor complex, transferase-transferase inhibitor complex, transferase, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Rattus norvegicus (Rat) More |
| Total number of polymer chains | 2 |
| Total formula weight | 93654.85 |
| Authors | Hruza, A.,Strickland, C.L. (deposition date: 2021-07-29, release date: 2021-09-08, Last modification date: 2023-10-18) |
| Primary citation | Bukhtiyarova, M.,Cook, E.M.,Hancock, P.J.,Hruza, A.W.,Shaw, A.W.,Adam, G.C.,Barnard, R.J.O.,McKenna, P.M.,Holloway, M.K.,Bell, I.M.,Carroll, S.,Cornella-Taracido, I.,Cox, C.D.,Kutchukian, P.S.,Powell, D.A.,Strickland, C.,Trotter, B.W.,Tudor, M.,Wolkenberg, S.,Li, J.,Tellers, D.M. Discovery of an Anion-Dependent Farnesyltransferase Inhibitor from a Phenotypic Screen. ACS Med Chem Lett, 12:99-106, 2021 Cited by PubMed Abstract: By employing a phenotypic screen, a set of compounds, exemplified by , 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 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 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 binds together with the anion in the active site to inhibit farnesyl transferase. Implications for phenotypic screening deconvolution and HIV reactivation are discussed. PubMed: 33488970DOI: 10.1021/acsmedchemlett.0c00551 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.978 Å) |
Structure validation
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