Structural basis for cell type specific DNA binding of C/EBPβ: The case of cell cycle inhibitor p15INK4b promoter

•Members of the C/EBP family control gene expression in a tissue and cell-type dependent manner. Genome-wide studies established that their genomic occupancy and cell-type-specificity depends on the local DNA sequence of the C/EBP binding motif.•In the p15INK4b promoter in epithelial cells, the C/EBP binding site, CTTAA•GAAAG, differs from the canonical, highest affinity ATTGC•GCAAT motif.•The X-ray crystal structure of the C/EBPβ bZIP domain bound to the p15INK4b promoter fragment shows that the GCGC-to-AAGA substitution generates changes in the intermolecular interactions in the protein-DNA interface that may discriminate against binding of certain members of the bZIP family of transcription factors.•CT/GA dinucleotides located at the 5’ ends of the double stranded element maintain local narrowing of the DNA minor groove width that appears necessary for DNA recognition.