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Energetics of a protein disorder–order transition in small molecule recognition
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Mendoza-Martinez, Cesar, Papadourakis, Michail, Llabrés, Salomé, Gupta, Arun, Barlow, Paul N. and Michel, Julien (2022) Energetics of a protein disorder–order transition in small molecule recognition. Chemical Science, 13 (18). pp. 5220-5229. doi:10.1039/D2SC00028H ISSN 2041-6520.
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Official URL: http://dx.doi.org/10.1039/D2SC00028H
Abstract
Many proteins recognise other proteins via mechanisms that involve the folding of intrinsically disordered regions upon complex formation. Here we investigate how the selectivity of a drug-like small molecule arises from its modulation of a protein disorder-to-order transition. Binding of the compound AM-7209 has been reported to confer order upon an intrinsically disordered ‘lid’ region of the oncoprotein MDM2. Calorimetric measurements revealed that truncation of the lid region of MDM2 increases the apparent dissociation constant of AM-7209 250-fold. By contrast, lid truncation has little effect on the binding of the ligand Nutlin-3a. Insights into these differential binding energetics were obtained via a complete thermodynamic analysis that featured adaptive absolute alchemical free energy of binding calculations with enhanced-sampling molecular dynamics simulations. The simulations reveal that in apo MDM2 the ordered lid state is energetically disfavoured. AM-7209, but not Nutlin-3a, shows a significant energetic preference for ordered lid conformations, thus shifting the balance towards ordering of the lid in the AM-7209/MDM2 complex. The methodology reported herein should facilitate broader targeting of intrinsically disordered regions in medicinal chemistry.
Item Type: | Journal Article | |||||||||||||||||||||
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Subjects: | Q Science > QD Chemistry | |||||||||||||||||||||
Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | |||||||||||||||||||||
Library of Congress Subject Headings (LCSH): | Proteins, Protein binding, Molecules, Pharmaceutical chemistry | |||||||||||||||||||||
Journal or Publication Title: | Chemical Science | |||||||||||||||||||||
Publisher: | Royal Society of Chemistry | |||||||||||||||||||||
ISSN: | 2041-6520 | |||||||||||||||||||||
Official Date: | 4 April 2022 | |||||||||||||||||||||
Dates: |
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Volume: | 13 | |||||||||||||||||||||
Number: | 18 | |||||||||||||||||||||
Page Range: | pp. 5220-5229 | |||||||||||||||||||||
DOI: | 10.1039/D2SC00028H | |||||||||||||||||||||
Status: | Peer Reviewed | |||||||||||||||||||||
Publication Status: | Published | |||||||||||||||||||||
Access rights to Published version: | Open Access (Creative Commons) | |||||||||||||||||||||
Date of first compliant deposit: | 9 June 2022 | |||||||||||||||||||||
Date of first compliant Open Access: | 14 June 2022 | |||||||||||||||||||||
RIOXX Funder/Project Grant: |
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