Binding of small molecule inhibitors to RNA polymerase-Spt5 complex impacts RNA and DNA stability

• DOI: 10.1007/s10822-023-00543-z
• Publication Date: 2023-11-21T08:06:45Z
• Authors: Adan Gallardo; Bercem Dutagaci
• Keywords: Processivity; RNA polymerase II; Transcription

Spt5 is an elongation factor that associates with RNA polymerase II (Pol II) during transcription and has important functions in promoter-proximal pausing processivity. was also recognized for its roles the of expanded-repeat genes are related to neurodegenerative diseases. Recently, a set Spt5-Pol small molecule inhibitors (SPIs) were reported, which selectively inhibit mutant huntingtin gene transcription. Inhibition mechanisms as well interaction sites these SPIs Pol not entirely known. In this study, we predicted binding three selected at II-Spt5 interface by docking molecular dynamics simulations. Two molecules out demonstrated strong II, while other more loosely bound sampled multiple sites. Strongly indirectly affected DNA exit site became flexible stabilized increased interactions Spt5. Our results suggest inhibition mechanism induced can be Spt5-nucleic acid interactions, altered some extent SPIs.