7RN5

Discovery of an Anion-Dependent Farnesyltransferase Inhibitor from a Phenotypic Screen

7RN5 の概要

• エントリーDOI: 10.2210/pdb7rn5/pdb
• 分子名称: Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha, Protein farnesyltransferase subunit beta, ACETYL GROUP, ... (8 entities in total)
• 機能のキーワード: protein inhibitor complex, transferase-transferase inhibitor complex, transferase, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Rattus norvegicus (Rat); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 93586.73

構造登録者

Hruza, A.,Strickland, C.L. (登録日: 2021-07-29, 公開日: 2021-09-08, 最終更新日: 2023-10-18)

主引用文献

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

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: 33488970
DOI: 10.1021/acsmedchemlett.0c00551

実験手法

X-RAY DIFFRACTION (2.28 Å)