Issue 4, 2018

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

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

Supplementary files

Article information

Article type
Edge Article
Submitted
02 Nov 2017
Accepted
01 Dec 2017
First published
04 Dec 2017
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2018,9, 1014-1021

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, 9, 1014 DOI: 10.1039/C7SC04749E

This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. You can use material from this article in other publications, without requesting further permission from the RSC, provided that the correct acknowledgement is given and it is not used for commercial purposes.

To request permission to reproduce material from this article in a commercial publication, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party commercial publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements