3D Model of Human O‐N‐Acetylglucosamine Hydrolase

Abstract

The post‐translational modification (PTM) of proteins enable cells to react promptly to internal and external signals through direct and progressive control of protein function. Addition of O‐linked‐n‐acetylglucosamine (O‐GlcNAc) to serine and threonine residues of cytoplasmic, nuclear and mitochondrial proteins is a nourishment and stress response PTM. O‐GlcNAcylation has been linked to several diseases such as diabetes and cancer. For example, increased O‐GlcNAcylation is directly linked to insulin resistance and to hyperglycemia‐induced glucose toxicity, two characteristics of diabetes and diabetic complications. O‐GlcNAc transferase (OGT) and O‐GlcNAcase (OGA) are enzymes that control the dynamic cycling of this PTM. Here, we have constructed a 3D model of human OGA bound to the transition state analog Thiamet‐G using Jmol and the PDB file 5M7S, a truncated version of the enzyme called Split1 (Roth et al. Nat. Chem. Biol. 2017). This protein is a functional homodimer that is stabilized by a helical bundle formed by helices from each subunit. Thiamet‐G fits in the substrate binding pocket formed by Cys215, Tyr298, and Trp278 and interacts with Gly67, Lys98, Asn280, Glu295, and Asn313 to form hydrogen bonds. Thiamet‐G also interacts with the catalytic residues Glu174 and Glu175. The focus of this project was to explore the protein structure of OGA and design and build a physical model that illustrated key functional features of the protein.Support or Funding InformationFunded in part by NSF‐DUE 1725940 for the CREST Project.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.