7OLU

Structure of the N-terminal domain of BC2L-C lectin (1-131) in complex with a synthetic beta-C-fucoside ligand

This is a non-PDB format compatible entry.

Summary for 7OLU

• Entry DOI: 10.2210/pdb7olu/pdb
• Related: 2WQ4 6TID 6TIG 7BFY
• Descriptor: Lectin, (2-(4-(beta-L-fucopyranosylethynyl)phenyl)-2-methylpropan-1-amine (3 entities in total)
• Functional Keywords: bacterial lectin, fucosides, glycomimetic, inhibitor, anti-microbial, sugar binding protein
• Biological source: Burkholderia cenocepacia (strain ATCC BAA-245 / DSM 16553 / LMG 16656 / NCTC 13227 / J2315 / CF5610)
• Total number of polymer chains: 1
• Total formula weight: 14330.33

Authors

Bermeo, R.,Varrot, A. (deposition date: 2021-05-20, release date: 2022-06-01, Last modification date: 2024-01-31)

Primary citation

Bermeo, R.,Lal, K.,Ruggeri, D.,Lanaro, D.,Mazzotta, S.,Vasile, F.,Imberty, A.,Belvisi, L.,Varrot, A.,Bernardi, A.
Targeting a Multidrug-Resistant Pathogen: First Generation Antagonists of Burkholderia cenocepacia 's BC2L-C Lectin.
Acs Chem.Biol., 17:2899-2910, 2022

PubMed Abstract: Multidrug-resistant pathogens such as have become a hazard in the context of healthcare-associated infections, especially for patients admitted with cystic fibrosis or immuno-compromising conditions. Like other opportunistic Gram-negative bacteria, this pathogen establishes virulence and biofilms through lectin-mediated adhesion. In particular, the BC2L-C is believed to cross-link human epithelial cells to during pulmonary infections. We aimed to obtain glycomimetic antagonists able to inhibit the interaction between the -terminal domain of BC2L-C (BC2L-C-Nt) and its target fucosylated human oligosaccharides. In a previous study, we identified by fragment virtual screening and validated a small set of molecular fragments that bind BC2L-C-Nt in the vicinity of the fucose binding site. Here, we report the rational design and synthesis of bifunctional - or -fucosides, generated by connecting these fragments to a fucoside core using a panel of rationally selected linkers. A modular route starting from two key fucoside intermediates was implemented for the synthesis, followed by evaluation of the new compounds as BC2L-C-Nt ligands with a range of techniques (surface plasmon resonance, isothermal titration calorimetry, saturation transfer difference NMR, differential scanning calorimetry, and X-ray crystallography). This study resulted in a hit molecule with an order of magnitude gain over the starting methyl fucoside and in two crystal structures of antagonist/lectin complexes.

PubMed: 36174276
DOI: 10.1021/acschembio.2c00532

Experimental method

X-RAY DIFFRACTION (1.793 Å)