6AU6

Crystal structure of GDP-bound human GNAS R201C mutant


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.200 
  • R-Value Work: 0.168 
  • R-Value Observed: 0.170 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Disease-Causing Mutations in the G Protein G alpha s Subvert the Roles of GDP and GTP.

Hu, Q.Shokat, K.M.

(2018) Cell 173: 1254-1264.e11

  • DOI: https://doi.org/10.1016/j.cell.2018.03.018
  • Primary Citation of Related Structures:  
    6AU6

  • PubMed Abstract: 

    The single most frequent cancer-causing mutation across all heterotrimeric G proteins is R201C in Gαs. The current model explaining the gain-of-function activity of the R201 mutations is through the loss of GTPase activity and resulting inability to switch off to the GDP state. Here, we find that the R201C mutation can bypass the need for GTP binding by directly activating GDP-bound Gαs through stabilization of an intramolecular hydrogen bond network. Having found that a gain-of-function mutation can convert GDP into an activator, we postulated that a reciprocal mutation might disrupt the normal role of GTP. Indeed, we found R228C, a loss-of-function mutation in Gαs that causes pseudohypoparathyroidism type 1a (PHP-Ia), compromised the adenylyl cyclase-activating activity of Gαs bound to a non-hydrolyzable GTP analog. These findings show that disease-causing mutations in Gαs can subvert the canonical roles of GDP and GTP, providing new insights into the regulation mechanism of G proteins.


  • Organizational Affiliation

    Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California-San Francisco, San Francisco, CA 94158, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Guanine nucleotide-binding protein G(s) subunit alpha isoforms short377Homo sapiensMutation(s): 1 
Gene Names: GNASGNAS1GSP
EC: 3.6.5
UniProt & NIH Common Fund Data Resources
Find proteins for P63092 (Homo sapiens)
Explore P63092 
Go to UniProtKB:  P63092
PHAROS:  P63092
GTEx:  ENSG00000087460 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP63092
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
GDP (Subject of Investigation/LOI)
Query on GDP

Download Ideal Coordinates CCD File 
B [auth A]GUANOSINE-5'-DIPHOSPHATE
C10 H15 N5 O11 P2
QGWNDRXFNXRZMB-UUOKFMHZSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
E [auth A],
F [auth A]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
D [auth A]CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
MG (Subject of Investigation/LOI)
Query on MG

Download Ideal Coordinates CCD File 
C [auth A]MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.200 
  • R-Value Work: 0.168 
  • R-Value Observed: 0.170 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 37.37α = 90
b = 85.58β = 90
c = 125.64γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
iMOSFLMdata reduction
SCALAdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Howard Hughes Medical Institute (HHMI)United States--
Damon Runyon Cancer Research FoundationUnited StatesDRG-[2229-15]

Revision History  (Full details and data files)

  • Version 1.0: 2018-05-09
    Type: Initial release
  • Version 1.1: 2018-05-30
    Changes: Data collection, Database references
  • Version 1.2: 2019-11-20
    Changes: Author supporting evidence
  • Version 1.3: 2023-10-04
    Changes: Data collection, Database references, Refinement description