2XR6

Crystal structure of the complex of the carbohydrate recognition domain of human DC-SIGN with pseudo trimannoside mimic.

Summary for 2XR6

• Entry DOI: 10.2210/pdb2xr6/pdb
• Related: 1K9I 1SL4 1SL5 2B6B 2XR5
• Descriptor: CD209 ANTIGEN, alpha-D-mannopyranose, dimethyl (1S,2S,4S,5S)-4,5-dihydroxycyclohexane-1,2-dicarboxylate, ... (7 entities in total)
• Functional Keywords: sugar binding protein, carbohydrate binding, mannose
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 20408.68

Authors

Thepaut, M.,Suitkeviciute, I.,Sattin, S.,Reina, J.,Bernardi, A.,Fieschi, F. (deposition date: 2010-09-10, release date: 2011-10-19, Last modification date: 2023-12-20)

Primary citation

Sutkeviciute, I.,Thepaut, M.,Sattin, S.,Berzi, A.,Mcgeagh, J.,Grudinin, S.,Weiser, J.,Le Roy, A.,Reina, J.J.,Rojo, J.,Clerici, M.,Bernardi, A.,Ebel, C.,Fieschi, F.
Unique Dc-Sign Clustering Activity of a Small Glycomimetic: A Lesson for Ligand Design.
Acs Chem.Biol., 9:1377-, 2014

PubMed Abstract: DC-SIGN is a dendritic cell-specific C-type lectin receptor that recognizes highly glycosylated ligands expressed on the surface of various pathogens. This receptor plays an important role in the early stages of many viral infections, including HIV, which makes it an interesting therapeutic target. Glycomimetic compounds are good drug candidates for DC-SIGN inhibition due to their high solubility, resistance to glycosidases, and nontoxicity. We studied the structural properties of the interaction of the tetrameric DC-SIGN extracellular domain (ECD), with two glycomimetic antagonists, a pseudomannobioside (1) and a linear pseudomannotrioside (2). Though the inhibitory potency of 2, as measured by SPR competition experiments, was 1 order of magnitude higher than that of 1, crystal structures of the complexes within the DC-SIGN carbohydrate recognition domain showed the same binding mode for both compounds. Moreover, when conjugated to multivalent scaffolds, the inhibitory potencies of these compounds became uniform. Combining isothermal titration microcalorimetry, analytical ultracentrifugation, and dynamic light scattering techniques to study DC-SIGN ECD interaction with these glycomimetics revealed that 2 is able, without any multivalent presentation, to cluster DC-SIGN tetramers leading to an artificially overestimated inhibitory potency. The use of multivalent scaffolds presenting 1 or 2 in HIV trans-infection inhibition assay confirms the loss of potency of 2 upon conjugation and the equal efficacy of chemically simpler compound 1. This study documents a unique case where, among two active compounds chemically derived, the compound with the lower apparent activity is the optimal lead for further drug development.

PubMed: 24749535
DOI: 10.1021/CB500054H

Experimental method

X-RAY DIFFRACTION (1.35 Å)