4LOJ

Crystal structure of mSting in complex with c[G(2',5')pA(3',5')p]


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.77 Å
  • R-Value Free: 0.212 
  • R-Value Work: 0.191 
  • R-Value Observed: 0.192 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Structure-Function Analysis of STING Activation by c[G(2',5')pA(3',5')p] and Targeting by Antiviral DMXAA.

Gao, P.Ascano, M.Zillinger, T.Wang, W.Dai, P.Serganov, A.A.Gaffney, B.L.Shuman, S.Jones, R.A.Deng, L.Hartmann, G.Barchet, W.Tuschl, T.Patel, D.J.

(2013) Cell 154: 748-762

  • DOI: https://doi.org/10.1016/j.cell.2013.07.023
  • Primary Citation of Related Structures:  
    4LOH, 4LOI, 4LOJ, 4LOK, 4LOL

  • PubMed Abstract: 

    Binding of dsDNA by cyclic GMP-AMP (cGAMP) synthase (cGAS) triggers formation of the metazoan second messenger c[G(2',5')pA(3',5')p], which binds the signaling protein STING with subsequent activation of the interferon (IFN) pathway. We show that human hSTING(H232) adopts a "closed" conformation upon binding c[G(2',5')pA(3',5')p] and its linkage isomer c[G(2',5')pA(2',5')p], as does mouse mSting(R231) on binding c[G(2',5')pA(3',5')p], c[G(3',5')pA(3',5')p] and the antiviral agent DMXAA, leading to similar "closed" conformations. Comparing hSTING to mSting, 2',5'-linkage-containing cGAMP isomers were more specific triggers of the IFN pathway compared to the all-3',5'-linkage isomer. Guided by structural information, we identified a unique point mutation (S162A) placed within the cyclic-dinucleotide-binding site of hSTING that rendered it sensitive to the otherwise mouse-specific drug DMXAA, a conclusion validated by binding studies. Our structural and functional analysis highlights the unexpected versatility of STING in the recognition of natural and synthetic ligands within a small-molecule pocket created by the dimerization of STING.


  • Organizational Affiliation

    Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Stimulator of interferon genes protein
A, B
188Mus musculusMutation(s): 0 
Gene Names: Tmem173Eris MitaMpysSting
UniProt & NIH Common Fund Data Resources
Find proteins for Q3TBT3 (Mus musculus)
Explore Q3TBT3 
Go to UniProtKB:  Q3TBT3
IMPC:  MGI:1919762
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ3TBT3
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
1SY
Query on 1SY

Download Ideal Coordinates CCD File 
C [auth B]cGAMP
C20 H24 N10 O13 P2
XRILCFTWUCUKJR-INFSMZHSSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
1SY PDBBind:  4LOJ Kd: 300 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.77 Å
  • R-Value Free: 0.212 
  • R-Value Work: 0.191 
  • R-Value Observed: 0.192 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 46.17α = 90
b = 46.48β = 90
c = 157.93γ = 90
Software Package:
Software NamePurpose
CBASSdata collection
PHASERphasing
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-08-14
    Type: Initial release
  • Version 1.1: 2013-10-02
    Changes: Database references
  • Version 1.2: 2015-08-05
    Changes: Non-polymer description
  • Version 1.3: 2024-02-28
    Changes: Data collection, Database references, Derived calculations, Structure summary