6W9M

Structure of the Ancestral Glucocorticoid Receptor 2 ligand binding domain in complex with vamorolone and SHP coregulator fragment

  • Classification: HORMONE
  • Organism(s): synthetic construct, Homo sapiens
  • Expression System: Escherichia coli
  • Mutation(s): No 

  • Deposited: 2020-03-23 Released: 2020-11-04 
  • Deposition Author(s): Liu, X., Ortlund, E.A.
  • Funding Organization(s): American Heart Association, National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.59 Å
  • R-Value Free: 0.220 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.189 

Starting Model: experimental
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Ligand Structure Quality Assessment 


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Literature

Disruption of a key ligand-H-bond network drives dissociative properties in vamorolone for Duchenne muscular dystrophy treatment.

Liu, X.Wang, Y.Gutierrez, J.S.Damsker, J.M.Nagaraju, K.Hoffman, E.P.Ortlund, E.A.

(2020) Proc Natl Acad Sci U S A 117: 24285-24293

  • DOI: https://doi.org/10.1073/pnas.2006890117
  • Primary Citation of Related Structures:  
    6W9K, 6W9L, 6W9M

  • PubMed Abstract: 

    Duchenne muscular dystrophy is a genetic disorder that shows chronic and progressive damage to skeletal and cardiac muscle leading to premature death. Antiinflammatory corticosteroids targeting the glucocorticoid receptor (GR) are the current standard of care but drive adverse side effects such as deleterious bone loss. Through subtle modification to a steroidal backbone, a recently developed drug, vamorolone, appears to preserve beneficial efficacy but with significantly reduced side effects. We use combined structural, biophysical, and biochemical approaches to show that loss of a receptor-ligand hydrogen bond drives these remarkable therapeutic effects. Moreover, vamorolone uniformly weakens coactivator associations but not corepressor associations, implicating partial agonism as the main driver of its dissociative properties. Additionally, we identify a critical and evolutionarily conserved intramolecular network connecting the ligand to the coregulator binding surface. Interruption of this allosteric network by vamorolone selectively reduces GR-driven transactivation while leaving transrepression intact. Our results establish a mechanistic understanding of how vamorolone reduces side effects, guiding the future design of partial agonists as selective GR modulators with an improved therapeutic index.


  • Organizational Affiliation

    Department of Biochemistry, Emory University, Atlanta, GA 30322.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Glucocorticoid Receptor251synthetic constructMutation(s): 0 
UniProt
Find proteins for A0A1X8XLE9 (unidentified)
Explore A0A1X8XLE9 
Go to UniProtKB:  A0A1X8XLE9
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupA0A1X8XLE9
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Nuclear receptor subfamily 0 group B member 211Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for Q15466 (Homo sapiens)
Explore Q15466 
Go to UniProtKB:  Q15466
PHAROS:  Q15466
GTEx:  ENSG00000131910 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ15466
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.59 Å
  • R-Value Free: 0.220 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.189 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 87.065α = 90
b = 52.854β = 116.394
c = 69.646γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling
HKL-2000phasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
American Heart AssociationUnited States17POST33660110
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)United StatesR01DK095750

Revision History  (Full details and data files)

  • Version 1.0: 2020-11-04
    Type: Initial release
  • Version 1.1: 2023-10-18
    Changes: Data collection, Database references, Refinement description