Structure-Based Evolution of Low Nanomolar O-GlcNAc Transferase Inhibitors
Sara E. S. Martin,Zhi-Wei Tan,Harri M. Itkonen,Damien Y. Duveau,Joao A. Paulo,John Janetzko,Paul L. Boutz,Lisa Törk,Frederick A. Moss,Craig J. Thomas,Steven P. Gygi,Michael B. Lazarus,Suzanne Walker +12 more
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TLDR
The structure-based evolution of OGT inhibitors culminating in compounds with low nanomolar inhibitory potency and on-target cellular activity are reported, providing insight into how to inhibit glycosyltransferases, a family of enzymes that has been notoriously refractory to inhibitor development.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.read more
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Journal ArticleDOI
Role of O-Linked N-Acetylglucosamine Protein Modification in Cellular (Patho)Physiology.
TL;DR: The current understanding of the processes involved in regulating O- GlcNAc turnover, the role of O-GlcNAcylation in regulating cellular physiology, and how dysregulation in O- GloverNAc cycling contributes to pathophysiological processes are outlined.
Journal ArticleDOI
Engineering a Proximity-Directed O-GlcNAc Transferase for Selective Protein O-GlcNAcylation in Cells.
Daniel H. Ramirez,Chanat Aonbangkhen,Hung-Yi Wu,Jeffrey A. Naftaly,Stephanie Tang,Timothy R. O’Meara,Christina M. Woo +6 more
TL;DR: These first proximity-directed OGT constructs provide a flexible strategy for targeting additional proteins and a template for further engineering of OGT and the O-GlcNAc proteome in the future.
Journal ArticleDOI
Analytical and Biochemical Perspectives of Protein O-GlcNAcylation.
Junfeng Ma,Ci Wu,Gerald W. Hart +2 more
TL;DR: A comprehensive review of protein O-linked β-N-acetylglucosamine (O-GlcNAc) modification from analytical and biochemical perspectives is presented in this article.
Journal ArticleDOI
High OGT activity is essential for MYC-driven proliferation of prostate cancer cells.
Harri M. Itkonen,Alfonso Urbanucci,Sara E. S. Martin,Aziz Khan,Anthony Mathelier,Bernd Thiede,Suzanne Walker,Ian G. Mills,Ian G. Mills,Ian G. Mills +9 more
TL;DR: It is shown that OGT is required for MYC-mediated stabilization of mitotic proteins, including Cyclin B1, and/or the increased translation of their coding transcripts, which implies that increased expression of mRNA is not always required to achieve increased protein expression and confer aggressive phenotype.
Journal ArticleDOI
Structural characterization of the O-GlcNAc cycling enzymes: insights into substrate recognition and catalytic mechanisms.
TL;DR: Recent successes in structural characterization of O-GlcNAc enzymes are reviewed and how this information has illuminated key features essential for catalysis and substrate recognition to expand the understanding of substrate specificity by each enzyme.
References
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Cross talk between O-GlcNAcylation and phosphorylation: roles in signaling, transcription, and chronic disease.
TL;DR: Recent glycomic analyses have shown that O-GlcNAcylation has surprisingly extensive cross talk with phosphorylation, where it serves as a nutrient/stress sensor to modulate signaling, transcription, and cytoskeletal functions.
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Xiaoyong Yang,Kevin Qian +1 more
TL;DR: New mechanisms and functions of O-GlcNAcylation that are emerging from these recent developments enable us to begin constructing a unified conceptual framework through which the significance of this modification in cellular and organismal physiology can be understood.
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A little sugar goes a long way: The cell biology of O-GlcNAc
Michelle R. Bond,John A. Hanover +1 more
TL;DR: The enzymes of O-GlcNAc cycling act preferentially on intrinsically disordered domains of target proteins impacting transcription, metabolism, apoptosis, organelle biogenesis, and transport.
Journal ArticleDOI
Structure of human O -GlcNAc transferase and its complex with a peptide substrate
TL;DR: The structures provide clues to the enzyme mechanism, show how OGT recognizes target peptide sequences, and reveal the fold of the unique domain between the two halves of the catalytic region will accelerate the rational design of biological experiments to investigate OGT’s functions.
Journal ArticleDOI
O-GlcNAc signalling: implications for cancer cell biology.
Chad Slawson,Gerald W. Hart +1 more
TL;DR: The current understanding of O-GlcNAcylation in cancer and its emerging functions in transcriptional regulation at the level of chromatin and transcription factors are summarized.