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Unexpected dynamics in femtomolar complexes of binding proteins with peptides

Cucuzza, Stefano; Sitnik, Malgorzata; Jurt, Simon; Michel, Erich; Dai, Wenzhao; Müntener, Thomas; Ernst, Patrick; Häussinger, Daniel; Plückthun, Andreas; Zerbe, Oliver (2023). Unexpected dynamics in femtomolar complexes of binding proteins with peptides. Nature Communications, 14(1):7823.

Abstract

Ultra-tight binding is usually observed for proteins associating with rigidified molecules. Previously, we demonstrated that femtomolar binders derived from the Armadillo repeat proteins (ArmRPs) can be designed to interact very tightly with fully flexible peptides. Here we show for ArmRPs with four and seven sequence-identical internal repeats that the peptide-ArmRP complexes display conformational dynamics. These dynamics stem from transient breakages of individual protein-residue contacts that are unrelated to overall unbinding. The labile contacts involve electrostatic interactions. We speculate that these dynamics allow attaining very high binding affinities, since they reduce entropic losses. Importantly, only NMR techniques can pick up these local events by directly detecting conformational exchange processes without complications from changes in solvent entropy. Furthermore, we demonstrate that the interaction surface of the repeat protein regularizes upon peptide binding to become more compatible with the peptide geometry. These results provide novel design principles for ultra-tight binders.

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Department of Biochemistry
07 Faculty of Science > Department of Biochemistry

07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:610 Medicine & health
540 Chemistry
570 Life sciences; biology
Scopus Subject Areas:Physical Sciences > General Chemistry
Life Sciences > General Biochemistry, Genetics and Molecular Biology
Physical Sciences > General Physics and Astronomy
Uncontrolled Keywords:biochemistry, biophysics, NMR, protein binders, protein design
Language:English
Date:28 November 2023
Deposited On:18 Dec 2023 09:06
Last Modified:30 Dec 2024 02:51
Publisher:Nature Publishing Group
ISSN:2041-1723
OA Status:Gold
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1038/s41467-023-43596-2
PubMed ID:38016954
Project Information:
  • Funder: SNSF
  • Grant ID: 122686
  • Project Title: Structure-based design of Armadillo Repeat Proteins as a modular recognition system for the sequence-specific binding of peptides
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  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)

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