Summary for 9EMQ
| Entry DOI | 10.2210/pdb9emq/pdb |
| Descriptor | DC-SIGN, CRD domain, CALCIUM ION, (2~{R},3~{S},4~{R},5~{S},6~{S})-2-(hydroxymethyl)-5-(4-phenyl-1,2,3-triazol-1-yl)-6-[[(3~{S})-piperidin-3-yl]methoxy]oxane-3,4-diol, ... (4 entities in total) |
| Functional Keywords | glyomimetic, dc-sign, sugar binding protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 18684.74 |
| Authors | |
| Primary citation | Nemli, D.D.,Jiang, X.,Jakob, R.P.,Gloder, L.M.,Schwardt, O.,Rabbani, S.,Maier, T.,Ernst, B.,Cramer, J. Thermodynamics-Guided Design Reveals a Cooperative Hydrogen Bond in DC-SIGN-targeted Glycomimetics. J.Med.Chem., 67:13813-13828, 2024 Cited by PubMed Abstract: Due to the shallow and hydrophilic binding sites of carbohydrate-binding proteins, the design of glycomimetics is often complicated by high desolvation costs as well as competition with solvent. Therefore, a careful optimization of interaction vectors and ligand properties is required in the design and optimization of glycomimetics. Here, we employ thermodynamics-guided design to optimize mannose-based glycomimetics targeting the human C-type lectin receptor dendritic cell-specific intercellular adhesion molecule 3 grabbing nonintegrin (DC-SIGN), a pathogenic host factor in viral infections. By exploring ligand rigidification and hydrogen bond engineering, a monovalent glycomimetic with an unprecedented affinity for DC-SIGN in the low μM range was discovered. A matched molecular pair analysis based on microcalorimetric data revealed a stereospecific hydrogen bond interaction with Glu358/Ser360 as the origin of this cooperative and enthalpically dominated interaction. This detailed insight into the binding mechanism paves the way for an improvement of monovalent glycomimetics targeting DC-SIGN. PubMed: 38771131DOI: 10.1021/acs.jmedchem.4c00623 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.8 Å) |
Structure validation
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