4QXO

Crystal structure of hSTING(group2) in complex with DMXAA


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.88 Å
  • R-Value Free: 0.218 
  • R-Value Work: 0.174 
  • R-Value Observed: 0.176 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Binding-Pocket and Lid-Region Substitutions Render Human STING Sensitive to the Species-Specific Drug DMXAA.

Gao, P.Zillinger, T.Wang, W.Ascano, M.Dai, P.Hartmann, G.Tuschl, T.Deng, L.Barchet, W.Patel, D.J.

(2014) Cell Rep 8: 1668-1676

  • DOI: https://doi.org/10.1016/j.celrep.2014.08.010
  • Primary Citation of Related Structures:  
    4QXO, 4QXP, 4QXQ, 4QXR

  • PubMed Abstract: 

    The drug DMXAA (5,6-dimethylxanthenone-4-acetic acid) showed therapeutic promise against solid tumors in mouse models but subsequently failed in human clinical trials. DMXAA was later discovered to activate mouse, but not human, STING, an adaptor protein in the cyclic dinucleotide cGAMP-mediated signaling pathway, inducing type I interferon expression. To facilitate the development of compounds that target human STING, we combined structural, biophysical, and cellular assays to study mouse and human chimeric proteins and their interaction with DMXAA. We identified a single substitution (G230I) that enables a DMXAA-induced conformational transition of hSTING from an inactive "open" to an active "closed" state. We also identified a substitution within the binding pocket (Q266I) that cooperates with G230I and the previously identified S162A binding-pocket point substitution, rendering hSTING highly sensitive to DMXAA. These findings should facilitate the reciprocal engineering of DMXAA analogs that bind and stimulate wild-type hSTING and their exploitation for vaccine-adjuvant and anticancer drug development.


  • 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 protein188Homo sapiensMutation(s): 7 
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 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
1YE
Query on 1YE

Download Ideal Coordinates CCD File 
B [auth A](5,6-dimethyl-9-oxo-9H-xanthen-4-yl)acetic acid
C17 H14 O4
XGOYIMQSIKSOBS-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
1YE BindingDB:  4QXO Kd: 130 (nM) from 1 assay(s)
EC50: 3.52e+4 (nM) from 1 assay(s)
Binding MOAD:  4QXO Kd: 3120 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.88 Å
  • R-Value Free: 0.218 
  • R-Value Work: 0.174 
  • R-Value Observed: 0.176 
  • Space Group: P 61 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 62.921α = 90
b = 62.921β = 90
c = 196.054γ = 120
Software Package:
Software NamePurpose
ADSCdata collection
PHASERphasing
PHENIXrefinement
RAPDdata reduction
RAPDdata 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: 2014-09-10
    Type: Initial release
  • Version 1.1: 2014-09-24
    Changes: Database references
  • Version 1.2: 2014-10-08
    Changes: Database references
  • Version 1.3: 2024-02-28
    Changes: Data collection, Database references, Derived calculations