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Designing interactions by control of protein–ligand complex conformation: tuning arginine–arene interaction geometry for enhanced electrostatic protein–ligand interactions

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Abstract

We investigated galectin-3 binding to 3-benzamido-2-O-sulfo-galactoside and -thiodigalactoside ligands using a combination of site-specific mutagenesis, X-ray crystallography, computational approaches, and binding thermodynamics measurements. The results reveal a conformational variability in a surface-exposed arginine (R144) side chain in response to different aromatic C3-substituents of bound galactoside-based ligands. Fluorinated C3-benzamido substituents induced a shift in the side-chain conformation of R144 to allow for an entropically favored electrostatic interaction between its guanidine group and the 2-O-sulfate of the ligand. By contrast, binding of ligands with non-fluorinated substituents did not trigger a conformational change of R144. Hence, a sulfate–arginine electrostatic interaction can be tuned by the choice of ligand C3-benzamido structures to favor specific interaction modes and geometries. These results have important general implications for ligand design, as the proper choice of arginine–aromatic interacting partners opens up for ligand-controlled protein conformation that in turn may be systematically exploited in ligand design.

Graphical abstract: Designing interactions by control of protein–ligand complex conformation: tuning arginine–arene interaction geometry for enhanced electrostatic protein–ligand interactions

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Publication details

The article was received on 02 Nov 2017, accepted on 01 Dec 2017 and first published on 04 Dec 2017


Article type: Edge Article
DOI: 10.1039/C7SC04749E
Citation: Chem. Sci., 2018, Advance Article
  • Open access: Creative Commons BY-NC license
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    Designing interactions by control of protein–ligand complex conformation: tuning arginine–arene interaction geometry for enhanced electrostatic protein–ligand interactions

    A.-L. Noresson, O. Aurelius, C. T. Öberg, O. Engström, A. P. Sundin, M. Håkansson, O. Stenström, M. Akke, D. T. Logan, H. Leffler and U. J. Nilsson, Chem. Sci., 2018, Advance Article , DOI: 10.1039/C7SC04749E

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