6i02

Structure of human D-glucuronyl C5 epimerase in complex with product

spinqualitylabelsall models 6i02, resolution 2.45Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6i02 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.45Å Ligands: BMA, CA, GNS, GOL, IDR, MAN, MES, NAG, P6G Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function GLCE_HUMAN Converts D-glucuronic acid residues adjacent to N-sulfate sugar residues to L-iduronic acid residues, both in maturing heparan sulfate (HS) and heparin chains. This is important for further modifications that determine the specificity of interactions between these glycosaminoglycans and proteins. Publication Abstract from PubMed Heparan sulfate (HS) is a linear, complex polysaccharide that modulates the biological activities of proteins through binding sites made by a series of Golgi-localized enzymes. Of these, glucuronyl C5-epimerase (Glce) catalyzes C5-epimerization of the HS component, d-glucuronic acid (GlcA), into l-iduronic acid (IdoA), which provides internal flexibility to the polymer and forges protein-binding sites to ensure polymer function. Here we report crystal structures of human Glce in the unbound state and of an inactive mutant, as assessed by real-time NMR spectroscopy, bound with a (GlcA-GlcNS)n substrate or a (IdoA-GlcNS)n product. Deep infiltration of the oligosaccharides into the active site cleft imposes a sharp kink within the central GlcNS-GlcA/IdoA-GlcNS trisaccharide motif. An extensive network of specific interactions illustrates the absolute requirement of N-sulfate groups vicinal to the epimerization site for substrate binding. At the epimerization site, the GlcA/IdoA rings are highly constrained in two closely related boat conformations, highlighting ring-puckering signatures during catalysis. The structure-based mechanism involves the two invariant acid/base residues, Glu499 and Tyr578, poised on each side of the target uronic acid residue, thus allowing reversible abstraction and readdition of a proton at the C5 position through a neutral enol intermediate, reminiscent of mandelate racemase. These structures also shed light on a convergent mechanism of action between HS epimerases and lyases and provide molecular frameworks for the chemoenzymatic synthesis of heparin or HS analogs. Substrate binding mode and catalytic mechanism of human heparan sulfate d-glucuronyl C5 epimerase.,Debarnot C, Monneau YR, Roig-Zamboni V, Delauzun V, Le Narvor C, Richard E, Henault J, Goulet A, Fadel F, Vives RR, Priem B, Bonnaffe D, Lortat-Jacob H, Bourne Y Proc Natl Acad Sci U S A. 2019 Mar 14. pii: 1818333116. doi:, 10.1073/pnas.1818333116. PMID:30872481 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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