2J62: Structure Of A Bacterial O-glcnacase In Complex With Glcnacstatin

Citation:
Abstract
Many phosphorylation signal transduction pathways in the eukaryotic cell are modulated by posttranslational modification of specific serines/threonines with N-acetylglucosamine (O-GlcNAc). Levels of O-GlcNAc on key proteins regulate biological processes as diverse as the cell cycle, insulin signaling, and protein degradation. The two enzymes involved in this dynamic and abundant modification are the O-GlcNAc transferase and O-GlcNAcase. Structural data have recently revealed that the O-GlcNAcase possesses an active site with significant structural similarity to that of the human lysosomal hexosaminidases HexA/HexB. PUGNAc, an O-GlcNAcase inhibitor widely used to raise levels of O-GlcNAc in human cell lines, also inhibits these hexosaminidases. Here, we have exploited recent structural information of an O-GlcNAcase-PUGNAc complex to design and synthesize a glucoimidazole-based inhibitor, GlcNAcstatin, which is a 5 pM competitive inhibitor of enzymes of the O-GlcNAcase family, shows 100000-fold selectivity over HexA/B, and binds to the O-GlcNAcase active site by mimicking the transition state as revealed by X-ray crystallography. This compound is able to raise O-GlcNAc levels in human HEK 293 and SH-SY5Y neuroblastoma cell lines and thus provides a novel, potent tool for the study of the role of O-GlcNAc in intracellular signal transduction pathways.
PDB ID: 2J62Download
MMDB ID: 44557
PDB Deposition Date: 2006/9/22
Updated in MMDB: 2007/10
Experimental Method:
x-ray diffraction
Resolution: 2.26  Å
Source Organism:
Similar Structures:
Biological Unit for 2J62: dimeric; determined by software (PISA)
Molecular Components in 2J62
Label Count Molecule
Proteins (2 molecules)
2
Hyaluronidase(Gene symbol: CPF_RS07030)
Molecule annotation
Chemicals (6 molecules)
1
4
2
2
* Click molecule labels to explore molecular sequence information.

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