5NPS

The human O-GlcNAc transferase in complex with a bisubstrate inhibitor

Summary for 5NPS

• Entry DOI: 10.2210/pdb5nps/pdb
• Descriptor: UDP-N-acetylglucosamine--peptide N-acetylglucosaminyltransferase 110 kDa subunit, 5,6-DIHYDRO-BENZO[H]CINNOLIN-3-YLAMINE, [[(2~{R},3~{S},4~{R},5~{R})-5-[2,4-bis(oxidanylidene)pyrimidin-1-yl]-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl] propyl hydrogen phosphate, ... (4 entities in total)
• Functional Keywords: o-glcnac transferase, gt-b, gt41, rossman-fold, active site, inhibitor, transferase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 81717.10

Authors

Rafie, K.,van Aalten, D. (deposition date: 2017-04-18, release date: 2018-05-16, Last modification date: 2024-11-20)

Primary citation

Rafie, K.,Gorelik, A.,Trapannone, R.,Borodkin, V.S.,van Aalten, D.M.F.
Thio-Linked UDP-Peptide Conjugates as O-GlcNAc Transferase Inhibitors.
Bioconjug. Chem., 29:1834-1840, 2018

PubMed Abstract: O-GlcNAc transferase (OGT) is an essential glycosyltransferase that installs the O-GlcNAc post-translational modification on the nucleocytoplasmic proteome. We report the development of S-linked UDP-peptide conjugates as potent bisubstrate OGT inhibitors. These compounds were assembled in a modular fashion by photoinitiated thiol-ene conjugation of allyl-UDP and optimal acceptor peptides in which the acceptor serine was replaced with cysteine. The conjugate VTPVC(S-propyl-UDP)TA ( K = 1.3 μM) inhibits the OGT activity in HeLa cell lysates. Linear fusions of this conjugate with cell penetrating peptides were explored as prototypes of cell-penetrant OGT inhibitors. A crystal structure of human OGT with the inhibitor revealed mimicry of the interactions seen in the pseudo-Michaelis complex. Furthermore, a fluorophore-tagged derivative of the inhibitor works as a high affinity probe in a fluorescence polarimetry hOGT assay.

PubMed: 29723473
DOI: 10.1021/acs.bioconjchem.8b00194

Experimental method

X-RAY DIFFRACTION (1.68 Å)