7FJH
LecA from Pseudomonas aeruginosa in complex with 4-Phenylbutyryl hydroxamic acid (CAS: 32153-46-1)
Summary for 7FJH
| Entry DOI | 10.2210/pdb7fjh/pdb |
| Descriptor | PA-I galactophilic lectin, N-oxidanyl-4-phenyl-butanamide, CALCIUM ION, ... (4 entities in total) |
| Functional Keywords | calcium-binding lectins, glycomimetics, sugar binding protein |
| Biological source | Pseudomonas aeruginosa |
| Total number of polymer chains | 4 |
| Total formula weight | 51599.29 |
| Authors | Shanina, S.,Kuhaudomlarp, S.,Siebs, E.,Fuchsberger, F.,Denis, M.,da Silva Figueiredo Celstino Gomes, P.,Clausen, M.H.,Seeberger, P.H.,Rognan, D.,Titz, A.,Imberty, A.,Rademacher, C. (deposition date: 2021-08-04, release date: 2022-06-08, Last modification date: 2023-11-29) |
| Primary citation | Shanina, E.,Kuhaudomlarp, S.,Siebs, E.,Fuchsberger, F.F.,Denis, M.,da Silva Figueiredo Celestino Gomes, P.,Clausen, M.H.,Seeberger, P.H.,Rognan, D.,Titz, A.,Imberty, A.,Rademacher, C. Targeting undruggable carbohydrate recognition sites through focused fragment library design. Commun Chem, 5:64-64, 2022 Cited by PubMed Abstract: Carbohydrate-protein interactions are key for cell-cell and host-pathogen recognition and thus, emerged as viable therapeutic targets. However, their hydrophilic nature poses major limitations to the conventional development of drug-like inhibitors. To address this shortcoming, four fragment libraries were screened to identify metal-binding pharmacophores (MBPs) as novel scaffolds for inhibition of Ca-dependent carbohydrate-protein interactions. Here, we show the effect of MBPs on the clinically relevant lectins DC-SIGN, Langerin, LecA and LecB. Detailed structural and biochemical investigations revealed the specificity of MBPs for different Ca-dependent lectins. Exploring the structure-activity relationships of several fragments uncovered the functional groups in the MBPs suitable for modification to further improve lectin binding and selectivity. Selected inhibitors bound efficiently to DC-SIGN-expressing cells. Altogether, the discovery of MBPs as a promising class of Ca-dependent lectin inhibitors creates a foundation for fragment-based ligand design for future drug discovery campaigns. PubMed: 36697615DOI: 10.1038/s42004-022-00679-3 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.79 Å) |
Structure validation
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