6ZZW

Structure of the N terminal domain of Bc2L-C lectin (1-131) in complex with Globo H (H-type 3) and CAS No 912569-62-1

Summary for 6ZZW

• Entry DOI: 10.2210/pdb6zzw/pdb
• Descriptor: Lectin, alpha-L-fucopyranose-(1-2)-beta-D-galactopyranose-(1-3)-2-acetamido-2-deoxy-beta-D-galactopyranose-(1-3)-alpha-D-galactopyranose-(1-4)-beta-D-galactopyranose, alpha-L-fucopyranose-(1-2)-beta-D-galactopyranose-(1-3)-2-acetamido-2-deoxy-beta-D-galactopyranose-(1-3)-alpha-D-galactopyranose, ... (6 entities in total)
• Functional Keywords: lectins, drug resistance, glycomimetics, anti-adhesive therapy, drug design, fragment based screening, sugar binding protein
• Biological source: Burkholderia cenocepacia (strain ATCC BAA-245 / DSM 16553 / LMG 16656 / NCTC 13227 / J2315 / CF5610)
• Total number of polymer chains: 3
• Total formula weight: 45016.69

Authors

Lal, K.,Bermeo, R.,Imberty, A.,Varrot, A. (deposition date: 2020-08-05, release date: 2021-04-07, Last modification date: 2024-01-31)

Primary citation

Lal, K.,Bermeo, R.,Cramer, J.,Vasile, F.,Ernst, B.,Imberty, A.,Bernardi, A.,Varrot, A.,Belvisi, L.
Prediction and Validation of a Druggable Site on Virulence Factor of Drug Resistant Burkholderia cenocepacia*.
Chemistry, 27:10341-10348, 2021

PubMed Abstract: Burkholderia cenocepacia is an opportunistic Gram-negative bacterium that causes infections in patients suffering from chronic granulomatous diseases and cystic fibrosis. It displays significant morbidity and mortality due to extreme resistance to almost all clinically useful antibiotics. The bacterial lectin BC2L-C expressed in B. cenocepacia is an interesting drug target involved in bacterial adhesion and subsequent deadly infection to the host. We solved the first high resolution crystal structure of the apo form of the lectin N-terminal domain (BC2L-C-nt) and compared it with the ones complexed with carbohydrate ligands. Virtual screening of a small fragment library identified potential hits predicted to bind in the vicinity of the fucose binding site. A series of biophysical techniques and X-ray crystallographic screening were employed to validate the interaction of the hits with the protein domain. The X-ray structure of BC2L-C-nt complexed with one of the identified active fragments confirmed the ability of the site computationally identified to host drug-like fragments. The fragment affinity could be determined by titration microcalorimetry. These structure-based strategies further provide an opportunity to elaborate the fragments into high affinity anti-adhesive glycomimetics, as therapeutic agents against B. cenocepacia.

PubMed: 33769626
DOI: 10.1002/chem.202100252

Experimental method

X-RAY DIFFRACTION (1.9 Å)