Hosted by Prof. Vladimir Torbeev
Keywords: Intrinsically disordered proteins, Leucine Zippers, DNA mimics, Foldamers
Abstract:
Basic region leucine zipper (bZIP) transcription factors are central regulators of gene expression but remain challenging targets due to the intrinsic disorder of their DNA-binding regions in the absence of DNA. These regions only adopt a defined α-helical structure upon binding to their cognate DNA sequences, leaving no preorganized binding pocket for conventional inhibitors.
Taking inspiration form the B-DNA topology, we have designed and synthesized DNA mimic foldamers, which fold into a helix in solution. These synthetic supramolecular helices display their phosphonic side chains at the same positions of phosphates in natural B-DNA. We investigate whether this DNA mimicry strategy can be used to target sequence-selective bZIP transcription factors.
Using electrophoretic mobility shift assays and biolayer interferometry, we show that these foldamers bind leucine zipper transcription factors with sub-micromolar affinities and can compete with cognate DNA binding. Circular dichroism further reveals that foldamer binding induces and stabilizes α-helical structure in otherwise disordered bZIP domains.
Together, these results demonstrate that DNA mimic foldamers can overcome both intrinsic disorder and sequence selectivity, offering a new approach to bind transcription factors long considered “undruggable.”