9bdx

NF-kappaB RelA homo-dimer bound to CG-centric kappaB DNA

spinqualitylabelsall models 9bdx, resolution 3.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9bdx is a 4 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.6Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed The dimeric nuclear factor kappa B (NF-kappaB) transcription factors (TFs) regulate gene expression by binding to a variety of kappaB DNA elements with conserved G:C-rich flanking sequences enclosing a degenerate central region. Toward defining mechanistic principles of affinity regulated by degeneracy, we observed an unusual dependence of the affinity of RelA on the identity of the central base pair, which appears to be noncontacted in the complex crystal structures. The affinity of kappaB sites with A or T at the central position is ~10-fold higher than with G or C. The crystal structures of neither the complexes nor the free kappaB DNAs could explain the differences in affinity. Interestingly, differential dynamics of several residues were revealed in molecular dynamics simulation studies, where simulation replicates totaling 148 mus were performed on NF-kappaB:DNA complexes and free kappaB DNAs. Notably, Arg187 and Arg124 exhibited selectivity in transient interactions that orchestrated a complex interplay among several DNA-interacting residues in the central region. Binding and simulation studies with mutants supported these observations of transient interactions dictating specificity. In combination with published reports, this work provides insights into the nuanced mechanisms governing the discriminatory binding of NF-kappaB family TFs to kappaB DNA elements and sheds light on cancer pathogenesis of cRel, a close homolog of RelA. Transient interactions modulate the affinity of NF-kappaB transcription factors for DNA.,Li T, Shahabi S, Biswas T, Tsodikov OV, Pan W, Huang DB, Wang VY, Wang Y, Ghosh G Proc Natl Acad Sci U S A. 2024 Jun 4;121(23):e2405555121. doi: , 10.1073/pnas.2405555121. Epub 2024 May 28. PMID:38805268 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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