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; U J Nilsson

doi:10.1039/c7sc04749e

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

Chem Sci. 2017 Dec 4;9(4):1014-1021. doi: 10.1039/c7sc04749e. eCollection 2018 Jan 28.

Authors

A-L Noresson¹, O Aurelius², C T Öberg¹, O Engström¹, A P Sundin¹, M Håkansson³, O Stenström⁴, M Akke⁴, D T Logan^{2

3}, H Leffler⁵, U J Nilsson¹

Affiliations

¹ Centre for Analysis and Synthesis , Department of Chemistry , Lund University , Box 124 , SE-221 00 Lund , Sweden . Email: ulf.nilsson@chem.lu.se.
² Section for Biochemistry and Structural Biology , Center for Molecular Protein Science , Department of Chemistry , Lund University , Box 124 , SE-221 00 Lund , Sweden.
³ SARomics Biostructures AB , Medicon Village , SE-223 81 Lund , Sweden.
⁴ Biophysical Chemistry , Center for Molecular Protein Science , Department of Chemistry , Lund University , Box 124 , SE-221 00 Lund , Sweden.
⁵ Department of Laboratory Medicine , Section MIG , Lund University , Sölvegatan 23, SE-223 62 , Lund , Sweden.

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.