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Conformational Selection in a Protein-Protein Interaction Revealed by Dynamic Pathway Analysis.

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Publication date 2016
Author Chakrabarti Kalyan S, Agafonov Roman V, Pontiggia Francesco, Otten Renee, Higgins Matthew K, Schertler Gebhard F X, Oprian Daniel D, Kern Dorothee,
Project NMR studies of GPCRs: Structure, dynamics and interactions with ligands and signaling proteins
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Original article (peer-reviewed)

Journal Cell reports
Volume (Issue) 14(1)
Page(s) 32 - 42
Title of proceedings Cell reports
DOI 10.1016/j.celrep.2015.12.010

Open Access

Abstract

Molecular recognition plays a central role in biology, and protein dynamics has been acknowledged to be important in this process. However, it is highly debated whether conformational changes happen before ligand binding to produce a binding-competent state (conformational selection) or are caused in response to ligand binding (induced fit). Proposals for both mechanisms in protein/protein recognition have been primarily based on structural arguments. However, the distinction between them is a question of the probabilities of going via these two opposing pathways. Here, we present a direct demonstration of exclusive conformational selection in protein/protein recognition by measuring the flux for rhodopsin kinase binding to its regulator recoverin, an important molecular recognition in the vision system. Using nuclear magnetic resonance (NMR) spectroscopy, stopped-flow kinetics, and isothermal titration calorimetry, we show that recoverin populates a minor conformation in solution that exposes a hydrophobic binding pocket responsible for binding rhodopsin kinase. Protein dynamics in free recoverin limits the overall rate of binding.
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