01994nas a2200169   4500008004100000022001400041245014800055210006900203260000900272300001400281490000800295520133600303100002201639700002001661700001501681856012801696       2024                        eng d  a1520-610600aCharacterization of the conformational hotspots of the RNA-dependent RNA polymerase complex identifies a unique structural malleability of nsp80 aCharacterization of the conformational hotspots of the RNAdepend  cOCT   a9959-99750 v1283 a<p>
	Several antiviral therapeutic approaches have been targeted toward the RNA-dependent RNA polymerase (RdRp) complex that is involved in viral genome replication. In SARS-CoV-2, although the RdRp is a multiprotein complex, the focus has been on the ligand binding catalytic core (nonstructural protein nsp12), and not the multiprotein functional dynamics. In this study, we focus on the conformational ensembles of the RdRp complex and their modulation by the presence of RNA, performing comprehensive microsecond-scale atomistic simulations of the apo- and RNA-bound complex. We delineate the differential impact of RNA on the constituent proteins, such as conformational polymorphisms, dominant segment-specific fluctuations, and the switch in dynamical crosstalk within the complex. We distinguish dynamical signatures of nsp7, nsp8, and nsp12 in the apo-state that are reduced in the presence of the RNA and appear to ``prime'' the complex for activity. Importantly, we identify a unique structural malleability of the nsp8 protein with high conformational heterogeneity in the apo state, especially at three sites (Y71 for nsp8A, and D52 and A66 for nsp8B). Our work highlights the functional implications of the polymorphism of nsp8 structures and reveals possibilities for the development of allosteric inhibitors.</p>
1 aGharui, Sowmomita1 aSengupta, Durba1 aDas, Atanu  uhttps://library.ncl.res.in/content/characterization-conformational-hotspots-rna-dependent-rna-polymerase-complex-identifies02232nas a2200229   4500008004100000022001400041245007800055210006900133260000800202300001200210490000700222520147600229653002901705653001701734653003501751653002401786653002401810653002501834100002201859700002001881856010101901       2025                        eng d  a0887-358500aMolecular interactions of the pioneer transcription factor GATA3 With DNA0 aMolecular interactions of the pioneer transcription factor GATA3  cFEB  a555-5660 v933 a<p>
	The GATA3 transcription factor is a pioneer transcription factor that is critical in the development, proliferation, and maintenance of several immune cell types. Identifying the detailed conformational dynamics and interactions of this transcription factor, as well as its clinically important population variants will allow us to unravel its mode of action. In this study, we analyze the molecular interactions of the GATA3 transcription factor bound to dsDNA as well as three clinically important population variants by atomistic molecular dynamics simulations. We identify the effect of the variants on the DNA conformational dynamics and delineate the differences compared to the wildtype transcription factor that could be related to impaired function. We highlight the structural plasticity in the binding of the GATA3 transcription factor and identify important DNA-protein contacts. Although the DNA-protein contacts are persistent and appear to be stable, they exhibit nanosecond timescale fluctuations and several binding/unbinding events. Further, we identify differential DNA binding in the three variants and show that the N-terminal binding is reduced in two of the variants. Our results indicate that reduced minor groove width and DNA diameter are important hallmarks for the binding of GATA3. Our work is an important step towards understanding the functional dynamics of the GATA3 protein and its clinically significant population variants.</p>
10aDNA-protein interactions10aGATA protein10aMolecular dynamics simulations10amolecular mechanism10apopulation variants10atranscription factor1 aGharui, Sowmomita1 aSengupta, Durba  uhttps://library.ncl.res.in/content/molecular-interactions-pioneer-transcription-factor-gata3-dna