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

TY - JOUR

T1 - Molecular driving force of a small molecule-induced protein disorder-order transition

AU - Mendoza-Martinez, Cesar

AU - Gupta, Arun A.

AU - Llabrés, Salomé

AU - Barlow, Paul N.

AU - Michel, Julien

N1 - Publisher Copyright: © The Author(s) 2026.

PY - 2026/2/3

Y1 - 2026/2/3

N2 - 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. (Figure presented.)

AB - 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. (Figure presented.)

UR - https://www.scopus.com/pages/publications/105029178719

U2 - 10.1038/s42004-025-01869-5

DO - 10.1038/s42004-025-01869-5

M3 - Article

C2 - 41535595

AN - SCOPUS:105029178719

VL - 9

SP - 1

EP - 10

JO - Communications Chemistry

JF - Communications Chemistry

IS - 1

M1 - 65

ER -