5NPR

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


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.236 
  • R-Value Work: 0.205 
  • R-Value Observed: 0.206 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Thio-Linked UDP-Peptide Conjugates as O-GlcNAc Transferase Inhibitors.

Rafie, K.Gorelik, A.Trapannone, R.Borodkin, V.S.van Aalten, D.M.F.

(2018) Bioconjug Chem 29: 1834-1840

  • DOI: https://doi.org/10.1021/acs.bioconjchem.8b00194
  • Primary Citation of Related Structures:  
    5NPR, 5NPS

  • 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 i = 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.


  • Organizational Affiliation

    Division of Gene Regulation and Expression, School of Life Sciences , University of Dundee , DD1 5EH Dundee , U.K.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
UDP-N-acetylglucosamine--peptide N-acetylglucosaminyltransferase 110 kDa subunit717Homo sapiensMutation(s): 0 
Gene Names: OGT
EC: 2.4.1.255
UniProt & NIH Common Fund Data Resources
Find proteins for O15294 (Homo sapiens)
Explore O15294 
Go to UniProtKB:  O15294
PHAROS:  O15294
GTEx:  ENSG00000147162 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO15294
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
bisubstrate inhibitorB [auth E]9synthetic constructMutation(s): 0 
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
94T
Query on 94T

Download Ideal Coordinates CCD File 
D [auth E][[(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
C12 H20 N2 O12 P2
INDMXLOHISKOMT-QCNRFFRDSA-N
K
Query on K

Download Ideal Coordinates CCD File 
C [auth A]POTASSIUM ION
K
NPYPAHLBTDXSSS-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.236 
  • R-Value Work: 0.205 
  • R-Value Observed: 0.206 
  • Space Group: F 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 138.038α = 90
b = 150.951β = 90
c = 200.54γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
Aimlessdata scaling
MOLREPphasing
Cootmodel building

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Wellcome TrustUnited Kingdom110061

Revision History  (Full details and data files)

  • Version 1.0: 2018-05-16
    Type: Initial release
  • Version 1.1: 2018-06-27
    Changes: Data collection, Database references
  • Version 1.2: 2024-01-17
    Changes: Data collection, Database references, Derived calculations, Refinement description