5VDR

Human cyclic GMP-AMP synthase (cGAS) in complex with 3',3'-cdIMP


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.04 Å
  • R-Value Free: 0.254 
  • R-Value Work: 0.208 
  • R-Value Observed: 0.210 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

The catalytic mechanism of cyclic GMP-AMP synthase (cGAS) and implications for innate immunity and inhibition.

Hall, J.Ralph, E.C.Shanker, S.Wang, H.Byrnes, L.J.Horst, R.Wong, J.Brault, A.Dumlao, D.Smith, J.F.Dakin, L.A.Schmitt, D.C.Trujillo, J.Vincent, F.Griffor, M.Aulabaugh, A.E.

(2017) Protein Sci 26: 2367-2380

  • DOI: https://doi.org/10.1002/pro.3304
  • Primary Citation of Related Structures:  
    5VDO, 5VDP, 5VDQ, 5VDR, 5VDS, 5VDT, 5VDU, 5VDV, 5VDW

  • PubMed Abstract: 

    Cyclic GMP-AMP synthase (cGAS) is activated by ds-DNA binding to produce the secondary messenger 2',3'-cGAMP. cGAS is an important control point in the innate immune response; dysregulation of the cGAS pathway is linked to autoimmune diseases while targeted stimulation may be of benefit in immunoncology. We report here the structure of cGAS with dinucleotides and small molecule inhibitors, and kinetic studies of the cGAS mechanism. Our structural work supports the understanding of how ds-DNA activates cGAS, suggesting a site for small molecule binders that may cause cGAS activation at physiological ATP concentrations, and an apparent hotspot for inhibitor binding. Mechanistic studies of cGAS provide the first kinetic constants for 2',3'-cGAMP formation, and interestingly, describe a catalytic mechanism where 2',3'-cGAMP may be a minor product of cGAS compared with linear nucleotides.


  • Organizational Affiliation

    Worldwide Medicinal Chemistry, Pfizer, Eastern Point Road, Groton, Connecticut, 06340.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Cyclic GMP-AMP synthase
A, B
363Homo sapiensMutation(s): 0 
Gene Names: MB21D1C6orf150
EC: 2.7.7.86
UniProt & NIH Common Fund Data Resources
Find proteins for Q8N884 (Homo sapiens)
Explore Q8N884 
Go to UniProtKB:  Q8N884
PHAROS:  Q8N884
GTEx:  ENSG00000164430 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ8N884
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.04 Å
  • R-Value Free: 0.254 
  • R-Value Work: 0.208 
  • R-Value Observed: 0.210 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 215.528α = 90
b = 48.395β = 109.89
c = 89.099γ = 90
Software Package:
Software NamePurpose
Aimlessdata scaling
PHENIXrefinement
PDB_EXTRACTdata extraction
Aimlessdata reduction
REFMACphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-09-27
    Type: Initial release
  • Version 1.1: 2017-10-04
    Changes: Database references
  • Version 1.2: 2017-12-06
    Changes: Database references
  • Version 1.3: 2023-10-04
    Changes: Data collection, Database references, Refinement description, Structure summary