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Heparanase binds substrate via a dynamic binding mechanism

Human heparanase (HPSE) cleaves heparan sulfate (HS) localized in the extracellular matrix allowing immune response to occur as well as cell proliferation and angiogenesis. On the other hand, increased HPSE activity promotes a variety of pathological conditions such as arterial thrombosis and tumor metastasis[1], making HPSE an important drug target. Although crystal structures of HSPE are available[2], the nature of interactions with its very flexible and highly negatively charged polysaccharide substrate HS is not fully understood. To better understand processes that govern substrate recognition, we have explored the ligand binding mechanism of HPSE by analysing its conformational landscape with molecular dynamics (MD) simulations and multi- conformer models generated by crystallographic ensemble refinement. Our results imply that HS binding to HPSE is a complex process. Heparan sulfate is stabilized and immobilized at the active site, whereas the outer regions of the enzyme binding site in complex with HS are characterized with dynamic ionic interactions and exhibit substantial conformational flexibility (Fig. 1). This dynamic substrate binding mechanism allows HSPE to retain high affinity towards its substrate while minimizing the entropic costs associated with binding highly flexible molecules. [3]

Human heparanase, heparan sulfate, MD simulations

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