6MA4

Crystal structure of human O-GlcNAc transferase bound to a peptide from HCF-1 pro-repeat 2 (11-26) and inhibitor 3a

Summary for 6MA4

• Entry DOI: 10.2210/pdb6ma4/pdb
• Descriptor: UDP-N-acetylglucosamine--peptide N-acetylglucosaminyltransferase 110 kDa subunit, Host Cell Factor 1 peptide, 5-{2-[(1R)-2-{(carboxymethyl)[(thiophen-2-yl)methyl]amino}-2-oxo-1-{[(2-oxo-1,2-dihydroquinolin-6-yl)sulfonyl]amino}ethyl]phenoxy}pentanoic acid, ... (4 entities in total)
• Functional Keywords: ogt, o-glcnac, glycosyltransferase, enzyme-inhibitor complex, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 83210.79

Authors

Martin, S.E.S.,Lazarus, M.B.,Walker, S. (deposition date: 2018-08-25, release date: 2018-10-17, Last modification date: 2023-10-11)

Primary citation

Martin, S.E.S.,Tan, Z.W.,Itkonen, H.M.,Duveau, D.Y.,Paulo, J.A.,Janetzko, J.,Boutz, P.L.,Tork, L.,Moss, F.A.,Thomas, C.J.,Gygi, S.P.,Lazarus, M.B.,Walker, S.
Structure-Based Evolution of Low Nanomolar O-GlcNAc Transferase Inhibitors.
J. Am. Chem. Soc., 140:13542-13545, 2018

PubMed Abstract: Reversible glycosylation of nuclear and cytoplasmic proteins is an important regulatory mechanism across metazoans. One enzyme, O-linked N-acetylglucosamine transferase (OGT), is responsible for all nucleocytoplasmic glycosylation and there is a well-known need for potent, cell-permeable inhibitors to interrogate OGT function. Here we report the structure-based evolution of OGT inhibitors culminating in compounds with low nanomolar inhibitory potency and on-target cellular activity. In addition to disclosing useful OGT inhibitors, the structures we report provide insight into how to inhibit glycosyltransferases, a family of enzymes that has been notoriously refractory to inhibitor development.

PubMed: 30285435
DOI: 10.1021/jacs.8b07328

Experimental method

X-RAY DIFFRACTION (2 Å)