The interplay of protein–ligand and water‐mediated interactions shape affinity and selectivity in the LAO binding protein

Renan Vergara; Sergio Romero‐Romero; Isabel Velázquez‐López; Georgina Espinoza‐Pérez; Annia Rodríguez‐Hernández; Nancy O. Pulido; Alejandro Sosa‐Peinado; Adela Rodríguez‐Romero; Daniel Alejandro Fernández‐Velasco

doi:10.1111/febs.15019

journal article Aug 05, 2019

The interplay of protein–ligand and water‐mediated interactions shape affinity and selectivity in the LAO binding protein

Renan Vergara Sergio Romero‐Romero Isabel Velázquez‐López Georgina Espinoza‐Pérez Annia Rodríguez‐Hernández Nancy O. Pulido Alejandro Sosa‐Peinado Adela Rodríguez‐Romero

Daniel Alejandro Fernández‐Velasco

The FEBS Journal Vol. 287 No. 4 pp. 763-782 · Wiley

View at Publisher Save 10.1111/febs.15019

Abstract

The study of binding thermodynamics is essential to understand how affinity and selectivity are acquired in molecular complexes. Periplasmic binding proteins (PBPs) are macromolecules of biotechnological interest that bind a broad number of ligands and have been used to design biosensors. The lysine‐arginine‐ornithine binding protein (LAO) is a PBP of 238 residues that binds the basic amino acids l‐arginine and l‐histidine with nm and μm affinity, respectively. It has been shown that the affinity difference for arginine and histidine binding is caused by enthalpy, this correlates with the higher number of protein–ligand contacts formed with arginine. In order to elucidate the structural bases that determine binding affinity and selectivity in LAO, the contribution of protein–ligand contacts to binding energetics was assessed. To this end, an alanine scanning of the LAO‐binding site residues was performed and arginine and histidine binding were characterized by isothermal titration calorimetry and X‐ray crystallography. Although unexpected enthalpy and entropy changes were observed in some mutants, thermodynamic data correlated with structural information, especially, the binding heat capacity change. We found that selectivity is conferred by several residues rather than exclusive arginine–protein interactions. Furthermore, crystallographic structures revealed that protein–ligand contributions to binding thermodynamics are highly influenced by the solvent. Finally, we found a similar backbone conformation in all the closed structures obtained, but different structures in the open state, suggesting that the binding site residues of LAO play an important role in stabilizing not only the holo conformation, but also the apo state.DatabaseStructural data are available in the Protein Data Bank database under the accession numbers 6MLE, 6MLN, 6MLG, 6MKX, 6MLI, 6MLA, 6MKU, 6MKW, 6ML0, 6MLD, 6MLV, 6MLO, 6MLP, 6ML9, 6MLJ.

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Details

Published: Aug 05, 2019
Vol/Issue: 287(4)
Pages: 763-782
License: View

Authors

R

Renan Vergara

Laboratorio de Fisicoquímica e Ingeniería de Proteínas, Departamento de Bioquímica, Facultad de Medicina Universidad Nacional Autónoma de México Ciudad de México México

S

Sergio Romero‐Romero

Laboratorio de Fisicoquímica e Ingeniería de Proteínas, Departamento de Bioquímica, Facultad de Medicina Universidad Nacional Autónoma de México Ciudad de México México

I

Isabel Velázquez‐López

Laboratorio de Fisicoquímica e Ingeniería de Proteínas, Departamento de Bioquímica, Facultad de Medicina Universidad Nacional Autónoma de México Ciudad de México México

G

Georgina Espinoza‐Pérez

Laboratorio de Química de Biomacromoléculas 3, Departamento de Química de Biomacromoléculas, Instituto de Química Universidad Nacional Autónoma de México Ciudad de México México

A

Annia Rodríguez‐Hernández

Laboratorio de Química de Biomacromoléculas 3, Departamento de Química de Biomacromoléculas, Instituto de Química Universidad Nacional Autónoma de México Ciudad de México México

N

Nancy O. Pulido

Laboratorio de Fisicoquímica e Ingeniería de Proteínas, Departamento de Bioquímica, Facultad de Medicina Universidad Nacional Autónoma de México Ciudad de México México

A

Alejandro Sosa‐Peinado

Laboratorio de Fisicoquímica e Ingeniería de Proteínas, Departamento de Bioquímica, Facultad de Medicina Universidad Nacional Autónoma de México Ciudad de México México

A

Adela Rodríguez‐Romero

Laboratorio de Química de Biomacromoléculas 3, Departamento de Química de Biomacromoléculas, Instituto de Química Universidad Nacional Autónoma de México Ciudad de México México

D

Daniel Alejandro Fernández‐Velasco

Laboratorio de Fisicoquímica e Ingeniería de Proteínas, Departamento de Bioquímica, Facultad de Medicina Universidad Nacional Autónoma de México Ciudad de México México

Funding

Consejo Nacional de Ciencia y Tecnología Award: 254514

Cite This Article

Renan Vergara, Sergio Romero‐Romero, Isabel Velázquez‐López, et al. (2019). The interplay of protein–ligand and water‐mediated interactions shape affinity and selectivity in the LAO binding protein. The FEBS Journal, 287(4), 763-782. https://doi.org/10.1111/febs.15019

The interplay of protein–ligand and water‐mediated interactions shape affinity and selectivity in the LAO binding protein

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