4LOI

Crystal structure of hSTING(H232) in complex with c[G(2',5')pA(2',5')p]


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.89 Å
  • R-Value Free: 0.199 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.177 

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Ligand Structure Quality Assessment 


This is version 1.2 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
188Homo sapiensMutation(s): 0 
Gene Names: TMEM173ERISMITASTING
UniProt & NIH Common Fund Data Resources
Find proteins for Q86WV6 (Homo sapiens)
Explore Q86WV6 
Go to UniProtKB:  Q86WV6
PHAROS:  Q86WV6
GTEx:  ENSG00000184584 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ86WV6
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
1YC
Query on 1YC

Download Ideal Coordinates CCD File 
D [auth B]2-amino-9-[(1R,3R,6R,8R,9R,11S,14R,16R,17R,18R)-16-(6-amino-9H-purin-9-yl)-3,11,17,18-tetrahydroxy-3,11-dioxido-2,4,7,10,12,15-hexaoxa-3,11-diphosphatricyclo[12.2.1.1~6,9~]octadec-8-yl]-1,9-dihydro-6H-purin-6-one
C20 H24 N10 O13 P2
BQZWXNITEWDGCM-INFSMZHSSA-N
PO4
Query on PO4

Download Ideal Coordinates CCD File 
C [auth A]PHOSPHATE ION
O4 P
NBIIXXVUZAFLBC-UHFFFAOYSA-K
Binding Affinity Annotations 
IDSourceBinding Affinity
1YC BindingDB:  4LOI Kd: 2.87e+5 (nM) from 1 assay(s)
EC50: min: 20, max: 1.50e+5 (nM) from 10 assay(s)
PDBBind:  4LOI Kd: 170 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.89 Å
  • R-Value Free: 0.199 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.177 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 93.948α = 90
b = 116.408β = 90
c = 36.164γ = 90
Software Package:
Software NamePurpose
CBASSdata collection
PHASERphasing
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

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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: 2024-02-28
    Changes: Data collection, Database references, Derived calculations