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<p>The selectivity and affinity of numerous protein–protein interactions depends upon the folding of intrinsically disordered regions (IDRs) that accompanies complexation. Here we investigate how folding-on-binding of a protein IDR by small molecules is facilitated by synergestic exploitation of interactions with a folded protein region. To this end, the molecular driving forces that underpin ordering of the N-terminal intrinsically disordered ‘lid’ region of the oncoprotein MDM2 by the small molecule AM-7209 were elucidated by a combination of molecular dynamics simulations, calorimetry and NMR measurements. Strikingly, mutations of lid residues distant from the ligand-binding site modulate potency by up to three orders of magnitude. A key requirement for conversion of this IDR into an ordered motif is collective stabilisation of a network of non-polar contacts between a chlorophenyl moiety of AM-7209 and the lid residue I19 to overcome conformational entropy loss associated with folding of the IDR. Our findings underscore the crucial role that protein IDRs can play in drug-resistance mechanisms and expand strategies available to medicinal chemists for ligand optimisation endeavours.</p><p></p>

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Molecular driving force of a small molecule-induced protein disorder-order transition

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月14日

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  • Cesar Mendoza-Martinez,
  • Arun A. Gupta,
  • Salomé Llabrés,
  • Paul N. Barlow,
  • Julien Michel

摘要

The selectivity and affinity of numerous protein–protein interactions depends upon the folding of intrinsically disordered regions (IDRs) that accompanies complexation. Here we investigate how folding-on-binding of a protein IDR by small molecules is facilitated by synergestic exploitation of interactions with a folded protein region. To this end, the molecular driving forces that underpin ordering of the N-terminal intrinsically disordered ‘lid’ region of the oncoprotein MDM2 by the small molecule AM-7209 were elucidated by a combination of molecular dynamics simulations, calorimetry and NMR measurements. Strikingly, mutations of lid residues distant from the ligand-binding site modulate potency by up to three orders of magnitude. A key requirement for conversion of this IDR into an ordered motif is collective stabilisation of a network of non-polar contacts between a chlorophenyl moiety of AM-7209 and the lid residue I19 to overcome conformational entropy loss associated with folding of the IDR. Our findings underscore the crucial role that protein IDRs can play in drug-resistance mechanisms and expand strategies available to medicinal chemists for ligand optimisation endeavours.