Neutron Crystallography Maps the Interaction Landscape of Pseudomonas aeruginosa LecA with Deuterated Aromatic β-Galactoside
10 affiliations
- 1CERMAV
- 2CNRS
- 3Large Scale Structures Group
- 4Institut Laue-Langevin
- 5Institut de Chimie des Substances Naturelles, UPR 2301, CNRS, Université Paris-Saclay, 1 avenue de la Terrasse, Gif-sur-Yvette, France
- 6CEA, Département Médicaments et Technologies pour la Santé (DMTS
- 7SCBM
- 8Biology, Deuteration, Chemistry and Soft Matter Group
- 9Institut de Chimie Moléculaire et des Matériaux d'Orsay
- 10UFR des Sciences d'Orsay
Abstract
Aromatic derivatives of β-galactosides are potent inhibitors of the LecA lectin, a key virulence factor of Pseudomonas aeruginosa, involved in host recognition, tissue adhesion and biofilm formation. This opportunistic bacterial pathogen is considered a serious global health threat, particularly due to the emergence of multidrug-resistant strains. Anti-adhesive and anti-biofilm compounds represent promising alternatives or complements to conventional antibiotic therapies. The design of such pathoblockers requires detailed structural insights into their interactions with the target protein. Neutron macromolecular crystallography (NMX) provides complementary structural information to X-ray diffraction (XRD), by enabling the localization of hydrogen atoms, but typically requires the use of deuterium-labeled molecules. We developed a unique approach combining bacterial production of deuterated galactose and its functionalization with a deuterated phenyl group, resulting in the first synthesis of perdeuterated phenyl-β-galactoside, PheβGal-d16. The structure of the deuterated bacterial receptor LecA in complex with PheβGal-d16 was determined using neutron diffraction, providing experimental localization of hydrogen atoms involved in hydrophobic contacts with the Pro38 and Gln53 residues, and in the unusual T-shaped π-stacking interaction with His50. These observations rationalize the 10-fold affinity increase measured for an aromatic β-galactoside compared to galactose.
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BibTeX
@misc{arnaud2026neutron,
title = {{Neutron Crystallography Maps the Interaction Landscape of Pseudomonas aeruginosa LecA with Deuterated Aromatic β-Galactoside}},
author = {Theodore Arnaud and Delphine Carry and Chloé Tatol and Juliette M. Devos and Lukas Gajdos and Philippe Lesot and Sophie Feuillastre and Stéphanie Norsikian and Annabelle Varrot and Emeline Richard-Millot and Sébastien Vidal and Matthew P. Blakeley and Anne Imberty},
howpublished = {ChemRxiv},
year = {2026},
month = sep,
doi = {10.26434/chemrxiv.15009182/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009182/v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - UNPB
TI - Neutron Crystallography Maps the Interaction Landscape of Pseudomonas aeruginosa LecA with Deuterated Aromatic β-Galactoside
AU - Theodore Arnaud
AU - Delphine Carry
AU - Chloé Tatol
AU - Juliette M. Devos
AU - Lukas Gajdos
AU - Philippe Lesot
AU - Sophie Feuillastre
AU - Stéphanie Norsikian
AU - Annabelle Varrot
AU - Emeline Richard-Millot
AU - Sébastien Vidal
AU - Matthew P. Blakeley
AU - Anne Imberty
PY - 2026
DA - 2026/09/21
PB - ChemRxiv
DO - 10.26434/chemrxiv.15009182/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009182/v1
AB - Aromatic derivatives of β-galactosides are potent inhibitors of the LecA lectin, a key virulence factor of Pseudomonas aeruginosa, involved in host recognition, tissue adhesion and biofilm formation. This opportunistic bacterial pathogen is considered a serious global health threat, particularly due to the emergence of multidrug-resistant strains. Anti-adhesive and anti-biofilm compounds represent promising alternatives or complements to conventional antibiotic therapies. The design of such pathoblockers requires detailed structural insights into their interactions with the target protein. Neutron macromolecular crystallography (NMX) provides complementary structural information to X-ray diffraction (XRD), by enabling the localization of hydrogen atoms, but typically requires the use of deuterium-labeled molecules. We developed a unique approach combining bacterial production of deuterated galactose and its functionalization with a deuterated phenyl group, resulting in the first synthesis of perdeuterated phenyl-β-galactoside, PheβGal-d16. The structure of the deuterated bacterial receptor LecA in complex with PheβGal-d16 was determined using neutron diffraction, providing experimental localization of hydrogen atoms involved in hydrophobic contacts with the Pro38 and Gln53 residues, and in the unusual T-shaped π-stacking interaction with His50. These observations rationalize the 10-fold affinity increase measured for an aromatic β-galactoside compared to galactose.
ER -