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.”