2AA2

Mineralocorticoid Receptor with Bound Aldosterone


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.235 
  • R-Value Work: 0.214 
  • R-Value Observed: 0.214 

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Ligand Structure Quality Assessment 


This is version 1.6 of the entry. See complete history


Literature

A Ligand-mediated Hydrogen Bond Network Required for the Activation of the Mineralocorticoid Receptor

Bledsoe, R.K.Madauss, K.P.Holt, J.A.Apolito, C.J.Lambert, M.H.Pearce, K.H.Stanley, T.B.Stewart, E.L.Trump, R.P.Willson, T.M.Williams, S.P.

(2005) J Biol Chem 280: 31283-31293

  • DOI: https://doi.org/10.1074/jbc.M504098200
  • Primary Citation of Related Structures:  
    2AA2, 2AA5, 2AA6, 2AA7, 2AAX, 2AB2

  • PubMed Abstract: 

    Ligand binding is the first step in hormone regulation of mineralocorticoid receptor (MR) activity. Here, we report multiple crystal structures of MR (NR3C2) bound to both agonist and antagonists. These structures combined with mutagenesis studies reveal that maximal receptor activation involves an intricate ligand-mediated hydrogen bond network with Asn770 which serves dual roles: stabilization of the loop preceding the C-terminal activation function-2 helix and direct contact with the hormone ligand. In addition, most activating ligands hydrogen bond to Thr945 on helix 10. Structural characterization of the naturally occurring S810L mutant explains how stabilization of a helix 3/helix 5 interaction can circumvent the requirement for this hydrogen bond network. Taken together, these results explain the potency of MR activation by aldosterone, the weak activation induced by progesterone and the antihypertensive agent spironolactone, and the binding selectivity of cortisol over cortisone.


  • Organizational Affiliation

    Department of Gene Expression and Protein Biochemistry, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA. randy.k.bledsoe@gsk.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Mineralocorticoid receptor275Homo sapiensMutation(s): 1 
Gene Names: NR3C2MCRMLR
UniProt & NIH Common Fund Data Resources
Find proteins for P08235 (Homo sapiens)
Explore P08235 
Go to UniProtKB:  P08235
PHAROS:  P08235
GTEx:  ENSG00000151623 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP08235
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
AS4 BindingDB:  2AA2 Kd: 0.5 (nM) from 1 assay(s)
IC50: min: 0.31, max: 43 (nM) from 3 assay(s)
EC50: min: 0.18, max: 3.8 (nM) from 4 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.235 
  • R-Value Work: 0.214 
  • R-Value Observed: 0.214 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 92.617α = 90
b = 173.139β = 90
c = 42.166γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
CNXrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2005-07-26
    Type: Initial release
  • Version 1.1: 2007-10-16
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Non-polymer description, Version format compliance
  • Version 1.3: 2017-10-11
    Changes: Refinement description
  • Version 1.4: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Advisory, Data collection, Database references, Derived calculations, Structure summary
  • Version 1.5: 2021-10-20
    Changes: Database references, Structure summary
  • Version 1.6: 2024-02-14
    Changes: Data collection