2019
DOI: 10.1093/glycob/cwz047
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NMR and molecular modeling reveal specificity of the interactions between CXCL14 and glycosaminoglycans

Abstract: CXCL14, chemokine (C-X-C motif) ligand 14, is a novel highly conserved chemokine with unique features. Despite exhibiting the typical chemokine fold, it has a very short N-terminus of just two amino acid residues responsible for chemokine receptor activation. CXCL14 actively participates in homeostatic immune surveillance of skin and mucosae, is linked to metabolic disorders and fibrotic lung diseases and possesses strong anti-angiogenic properties in early tumor development. In this work, we investigated the … Show more

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Cited by 29 publications
(33 citation statements)
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“…Several clusters of docking solutions were obtained for each GAG tested. The polarity of the binding poses was analyzed because the orientation of the GAG chain was shown to be non-random for the IL-8 chemokine [7] and determinant for the binding specificity of the C-X-C motif chemokine ligand 14 [8], suggesting an important functional role of GAG polarity in their interactions with proteins. Then, for the most diverse binding poses within these clusters, molecular dynamics (MD) simulations were performed with binding free energy post-processing calculations and per residue binding free energy decomposition.…”
Section: Resultsmentioning
confidence: 99%
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“…Several clusters of docking solutions were obtained for each GAG tested. The polarity of the binding poses was analyzed because the orientation of the GAG chain was shown to be non-random for the IL-8 chemokine [7] and determinant for the binding specificity of the C-X-C motif chemokine ligand 14 [8], suggesting an important functional role of GAG polarity in their interactions with proteins. Then, for the most diverse binding poses within these clusters, molecular dynamics (MD) simulations were performed with binding free energy post-processing calculations and per residue binding free energy decomposition.…”
Section: Resultsmentioning
confidence: 99%
“…Whereas DS competes with HP for the same binding site on PCPE-1, CS6 binds to a different region, which would allow HP oligosaccharides to remain bound to the NTR domain. Similar computational approaches were successfully applied to demonstrate the experimentally proven differences in binding strength between DS and CS6 interacting via the same binding pose to IL-8 [7,32] In contrast, the binding differences for those GAGs were related to certain differences in the binding pose for CXCL14 [8]. This suggests that for protein-GAG complexes, the predictive power of the computational methods is dramatically dependent on the protein involved and the distribution of the clusters on its surface, which is, in turn, also sensitive to a particular clustering procedure.…”
Section: Resultsmentioning
confidence: 99%
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“…The underlying molecular mechanism may involve positive allosteric receptor modulation, although we were unable to demonstrate direct binding of CXCL14 to CCR7 or CXCR5. Since CXCL14 strongly interacts with proteoglycans ( 29 , 55 ), it is possible that CXCL14 targets carbohydrate modifications on cell surface proteins, including CCR7. Also, SPR spectroscopy monitors molecular interactions in real-time, which may be more sensitive than steady-state receptor binding protocols (e.g., flow cytometry) and, thus, explain our previous results with CXCR4.…”
Section: Discussionmentioning
confidence: 99%
“…Accordingly, the binding pose for heparin was suggested to be different from the binding poses of HA, CS-A/C, -D and DS. Moreover, it was proposed that different GAG sulphation patterns might confer specificity to the interaction (204).…”
Section: Consequences Of Cxcl14 Binding To Glycosaminoglycansmentioning
confidence: 99%