6HKI
Crystal structure of surface entropy mutant of human O-GlcNAc hydrolase
Summary for 6HKI
| Entry DOI | 10.2210/pdb6hki/pdb |
| Descriptor | Protein O-GlcNAcase (2 entities in total) |
| Functional Keywords | hydrolase, o-glcnac, deglycosylation, glycosidase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 205809.66 |
| Authors | Males, A.,Davies, G.J. (deposition date: 2018-09-06, release date: 2019-01-23, Last modification date: 2024-01-17) |
| Primary citation | Males, A.,Davies, G.J. Structural studies of a surface-entropy reduction mutant of O-GlcNAcase. Acta Crystallogr D Struct Biol, 75:70-78, 2019 Cited by PubMed Abstract: The enzyme O-GlcNAcase catalyses the removal of the O-GlcNAc co/post-translational modification in multicellular eukaryotes. The enzyme has become of acute interest given the intimate role of O-GlcNAcylation in tau modification and stability; small-molecular inhibitors of human O-GlcNAcase are under clinical assessment for the treatment of tauopathies. Given the importance of structure-based and mechanism-based inhibitor design for O-GlcNAcase, it was sought to test whether different crystal forms of the human enzyme could be achieved by surface mutagenesis. Guided by surface-entropy reduction, a Glu602Ala/Glu605Ala variant [on the Gly11-Gln396/Lys535-Tyr715 construct; Roth et al. (2017), Nature Chem. Biol. 13, 610-612] was obtained which led to a new crystal form of the human enzyme. An increase in crystal contacts stabilized disordered regions of the protein, enabling 88% of the structure to be modelled; only 83% was possible for the wild-type construct. Although the binding of the C-terminus was consistent with the wild type, Lys713 in monomer A was bound in the -1 subsite of the symmetry-related monomer A and the active sites of the B monomers were vacant. The new crystal form presents an opportunity for enhanced soaking experiments that are essential to understanding the binding mechanism and substrate specificity of O-GlcNAcase. PubMed: 30644846DOI: 10.1107/S2059798318016595 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.3 Å) |
Structure validation
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