Application of drug discovery software to the identification of heparin-binding sites on protein surfaces: a computational survey of the 4-helix cytokines

Mulloy, Barbara; Forster, Mark J.

doi:10.1080/08927020701784754

Cited by 26 publications

(45 citation statements)

References 48 publications

(60 reference statements)

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“…The potential of sclerostin to interact with heparin was assessed by a proven procedure that employs a rigid body docking protocol to identify heparin binding sites on proteins (62). This analysis strongly suggested the presence of an extensive heparin binding site.…”

Section: Resultsmentioning

confidence: 99%

Characterization of the Structural Features and Interactions of Sclerostin

Veverka

Henry

Slocombe

et al. 2009

Journal of Biological Chemistry

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214

109

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The secreted glycoprotein sclerostin has recently emerged as a key negative regulator of Wnt signaling in bone and has stimulated considerable interest as a potential target for therapeutics designed to treat conditions associated with low bone mass, such as osteoporosis. We have determined the structure of sclerostin, which resulted in the identification of a previously unknown binding site for heparin, suggestive of a functional role in localizing sclerostin to the surface of target cells. We have also mapped the interaction site for an antibody that blocks the inhibition of Wnt signaling by sclerostin. This shows minimal overlap with the heparin binding site and highlights a key role for this region of sclerostin in protein interactions associated with the inhibition of Wnt signaling. The conserved N-and C-terminal arms of sclerostin were found to be unstructured, highly flexible, and unaffected by heparin binding, which suggests a role in stabilizing interactions with target proteins.

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Section: Resultsmentioning

confidence: 99%

Characterization of the Structural Features and Interactions of Sclerostin

Veverka

Henry

Slocombe

et al. 2009

Journal of Biological Chemistry

Self Cite

214

109

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“…Modeling of Heparin-Hh and Heparin-Shh InteractionsDocking calculations were performed using the program Autodock as described previously (24). This protocol allows a simple and computationally inexpensive search of the whole protein surface for the optimum heparin-binding site, but it does not predict the "pose" of the ligand within the binding site and does not allow for any flexibility in the protein.…”

Section: Methodsmentioning

confidence: 99%

“…This was the case not only for the relatively short, partly flexible pentasaccharide ligands but also for the extended and rigid undecasaccharide structure. As the protein structure is rigid in the docking protocol used (24), the extended conformations of the N-terminal sequences in PDB codes 1VHH and 1MIN are retained in the final models of the docked complexes, which may well not be an accurate reflection of their behavior in solution.…”

Section: Molecular Modeling Of Shh-heparinmentioning

confidence: 99%

Two Distinct Sites in Sonic Hedgehog Combine for Heparan Sulfate Interactions and Cell Signaling Functions

Chang

Mulloy

Magee

et al. 2011

Journal of Biological Chemistry

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Background:The morphogen, sonic hedgehog, has important roles in development and disease and is in part dependent on heparan sulfate interactions. Results: Two sites in the protein are shown to contribute to heparan sulfate interactions and biological activity. Conclusion: A new site in sonic hedgehog is identified that regulates its biological activity. Significance: The data provide new insight into the important role of proteoglycan interactions with sonic hedgehog.

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“…For several heparin-binding ILs in this structural class, heparin binding sites were not predicted to be conserved; indeed, the predicted binding sites for IL-2, IL-3, IL-4, and IL-13 do not overlap (Mulloy and Forster, 2008). However, heparin-binding properties have been described for IL-2 (Najjam et al, 1998), IL-3 (Roberts et al, 1988), and IL-4 (Lortat-Jacob et al, 1997; den Dekker et al, 2008), among other ILs (Table 1).…”

Section: Heparin and Cytokines Growth Factors Selectins And Promentioning

confidence: 99%

“…Heparin binding properties have been predicted by molecular modeling for some of this family, and not for others (Mulloy and Forster, 2008). For example, although erythropoietin and thrombopoietin are both predicted to bind heparin, no reports of heparin interactions are available for either protein, possibly owing to glycosylation of the native proteins in contrast with the pure peptides used for the simulations.…”

Section: Heparin and Cytokines Growth Factors Selectins And Promentioning

confidence: 99%