Structural Modulation Study of Inhibitory Compounds for Ribonuclease H Activity of Human Immunodeficiency Virus Type 1 Reverse Transcriptase

Yanagita, Hiroshi; Fudo, Satoshi; Urano, Emiko; Ichikawa, Reiko; Ogata, Masakazu; Yokota, M; Murakami, Tsutomu; Wu, Honggui; Chiba, Joe; Komano, Jun; Hoshino, Tyuji

doi:10.1248/cpb.60.764

Cited by 10 publications

(9 citation statements)

References 36 publications

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“…Small molecular chemical compounds against Histagged FIR (His-FIR) and His-tagged FIRΔexon2 were screened among 23,275 natural chemicals of NPDepo (RIKEN Natural Products Depository) at RIKEN institutes (Wako, Saitama, Japan) as previously described 51 . In silico computer screening was performed to search fo synthesized chemicals that mimicked the structure of the identified compound using the Namiki database that was composed of commercially available chemicals 23 .…”

Section: In Silico Screening For Inhibitory Compounds Against Firδexomentioning

confidence: 99%

Post-transcriptional regulation of BRG1 by FIRΔexon2 in gastric cancer

et al. 2020

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Brahma-related gene 1 (BRG1), an ATPase subunit of the SWItch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex controls multipotent neural crest formation by regulating epithelial-mesenchymal transition (EMT)-related genes with adenosine triphosphate-dependent chromodomain-helicase DNA-binding protein 7 (CHD7). The expression of BRG1 engages in pre-mRNA splicing through interacting RNPs in cancers; however, the detailed molecular pathology of how BRG1and CHD7 relate to cancer development remains largely unveiled. This study demonstrated novel post-transcriptional regulation of BRG1 in EMT and relationship with FIRΔexon2, which is a splicing variant of the far-upstream element-binding protein (FUBP) 1-interacting repressor (FIR) lacking exon 2, which fails to repress c-myc transcription in cancers. Previously, we have reported that FIR complete knockout mice (FIR −/− ) was embryonic lethal before E9.5, suggesting FIR is crucial for development. FIRΔexon2 acetylated H3K27 on promoter of BRG1 by CHIP-sequence and suppressed BRG1 expression post-transcriptionally; herein BRG1 suppressed Snai1 that is a transcriptional suppressor of E-cadherin that prevents cancer invasion and metastasis. Ribosomal proteins, hnRNPs, splicing-related factors, poly (A) binding proteins, mRNA-binding proteins, tRNA, DEAD box, and WD-repeat proteins were identified as co-immunoprecipitated proteins with FIR and FIRΔexon2 by redoing exhaustive mass spectrometry analysis. Furthermore, the effect of FIRΔexon2 on FGF8 mRNA splicing was examined as an indicator of neural development due to impaired CHD7 revealed in CHARGE syndrome. Expectedly, siRNA of FIRΔexon2 altered FGF8 pre-mRNA splicing, indicated close molecular interaction among FIRΔexon2, BRG1 and CHD7. FIRΔexon2 mRNA was elevated in human gastric cancers but not in non-invasive gastric tumors in FIR +/ mice (K19-Wnt1/C2mE x FIR +/− ). The levels of FIR family (FIR, FIRΔexon2 and PUF60), BRG1, Snai1, FBW7, E-cadherin, c-Myc, cyclin-E, and SAP155 increased in the gastric tumors in FIR +/− mice compared to those expressed in wild-type mice. FIR family, Snai1, cyclin-E, BRG1, and c-Myc showed trends toward higher expression in larger tumors than in smaller tumors in Gan-mice (K19-Wnt1/C2mE). The expressions of BRG1 and Snai1 were positively correlated in the gastric tumors of the Gan-mice. Finally, BRG1 is a candidate substrate of F-box and WD-repeat domain-containing 7 (FBW7) revealed by three-dimensional crystal structure analysis that the U2AF-homology motif (UHM) of FIRΔexon2 interacted with tryptophan-425 and asparate-399 (WD)-like motif in the degron pocket of FBW7 as a UHM-ligand motif. Together, FIRΔexon2 engages in multi-step post-transcriptional regulation of BRG1, affecting EMT through the BRG1/Snai1/E-cadherin pathway and promoting tumor proliferation and invasion of gastric cancers.

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Section: In Silico Screening For Inhibitory Compounds Against Firδexomentioning

confidence: 99%

Post-transcriptional regulation of BRG1 by FIRΔexon2 in gastric cancer

et al. 2020

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“…11,20 However, there exists only a very limited number of studies that explore the structural dynamics of the RNH domain. 21 Investigation of the structural dynamics of RNH will provide highly valuable information for inhibitor design, e.g., mode of ligand recognition by the protein, structural changes upon ligand binding, all factors that influence the ligand binding affinity. In a previous study we have developed efficient virtual screening models 18 (e.g.…”

Section: Introductionmentioning

confidence: 99%

Binding free energy based structural dynamics analysis of HIV-1 RT RNase H–inhibitor complexes

2014

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Accurate prediction of binding free energies associated with small molecules binding to a receptor is a major challenge in drug design processes. To achieve this goal many computational methods have been developed ranging from highly efficient empirical based docking schemes to high accuracy methods based on e.g. free energy calculations. In this study, binding affinity predictions for a set of HIV-1 RNase H inhibitors have been performed using MM-PB(GB)/SA methods. The current study describes in detail how the choice of initial ligand structures, e.g. protonation states, impacts the predicted ranking of the compounds. In addition we study the structural dynamics of the RNase H complexes using molecular dynamics. The role of each residue contribution to the overall binding free energy is also explored and used to explain the variations in the inhibition potency. The results reported here can be useful for design of small molecules against RNase H activity in the development of effective drugs for HIV treatment.

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“…Screening Assay To find the inhibitory compounds for the enzymatic activity of MBLs, the inhibition rate was measured for about 600 in-house compounds. Most of the compounds were synthesized through the research of developing the inhibitors targeting the ribonuclease (RNase) H activity of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase 12,13) or the endonuclease activity of influenza virus polymerase. [14][15][16] As with the MBLs, both HIV-1 RNase H 17,18) and influenza endonuclease [19][20][21] activities are functionalized by two divalent metal ions located at their catalytic sites.…”

Section: Resultsmentioning

confidence: 99%