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

Noresson, A. L. LU ; Aurelius, O. LU ; Öberg, C. T. LU ; Engström, O.; Sundin, A. P. LU ; Håkansson, M.; Stenström, O. LU ; Akke, M. LU ; Logan, D. T. LU and Leffler, H. LU , et al. (2018) In Chemical Science 9(4). p.1014-1021
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... (More)

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.

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published
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Chemical Science
volume
9
issue
4
pages
8 pages
publisher
Royal Society of Chemistry
external identifiers
  • scopus:85041238128
ISSN
2041-6520
DOI
10.1039/c7sc04749e
language
English
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yes
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057402fb-c650-47c3-806f-fee5d3d2ca13
date added to LUP
2018-02-12 12:35:52
date last changed
2018-05-29 10:15:52
@article{057402fb-c650-47c3-806f-fee5d3d2ca13,
  abstract     = {<p>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.</p>},
  author       = {Noresson, A. L. and Aurelius, O. and Öberg, C. T. and Engström, O. and Sundin, A. P. and Håkansson, M. and Stenström, O. and Akke, M. and Logan, D. T. and Leffler, H. and Nilsson, U. J.},
  issn         = {2041-6520},
  language     = {eng},
  number       = {4},
  pages        = {1014--1021},
  publisher    = {Royal Society of Chemistry},
  series       = {Chemical Science},
  title        = {Designing interactions by control of protein-ligand complex conformation : Tuning arginine-arene interaction geometry for enhanced electrostatic protein-ligand interactions},
  url          = {http://dx.doi.org/10.1039/c7sc04749e},
  volume       = {9},
  year         = {2018},
}