5SYZ

Human Liver Receptor Homologue-1 (LRH-1) Bound to a RJW100 stereoisomer and a Fragment of TIF-2

  • Classification: NUCLEAR PROTEIN
  • Organism(s): Homo sapiens
  • Expression System: Enterobacteria phage L1
  • Mutation(s): No 

  • Deposited: 2016-08-12 Released: 2016-10-12 
  • Deposition Author(s): Ortlund, E.A., Mays, S.G.
  • Funding Organization(s): National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK), National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.93 Å
  • R-Value Free: 0.228 
  • R-Value Work: 0.205 
  • R-Value Observed: 0.206 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history


Literature

Crystal Structures of the Nuclear Receptor, Liver Receptor Homolog 1, Bound to Synthetic Agonists.

Mays, S.G.Okafor, C.D.Whitby, R.J.Goswami, D.Stec, J.Flynn, A.R.Dugan, M.C.Jui, N.T.Griffin, P.R.Ortlund, E.A.

(2016) J Biol Chem 291: 25281-25291

  • DOI: https://doi.org/10.1074/jbc.M116.753541
  • Primary Citation of Related Structures:  
    5L11, 5SYZ

  • PubMed Abstract: 

    Liver receptor homolog 1 (NR5A2, LRH-1) is an orphan nuclear hormone receptor that regulates diverse biological processes, including metabolism, proliferation, and the resolution of endoplasmic reticulum stress. Although preclinical and cellular studies demonstrate that LRH-1 has great potential as a therapeutic target for metabolic diseases and cancer, development of LRH-1 modulators has been difficult. Recently, systematic modifications to one of the few known chemical scaffolds capable of activating LRH-1 failed to improve efficacy substantially. Moreover, mechanisms through which LRH-1 is activated by synthetic ligands are entirely unknown. Here, we use x-ray crystallography and other structural methods to explore conformational changes and receptor-ligand interactions associated with LRH-1 activation by a set of related agonists. Unlike phospholipid LRH-1 ligands, these agonists bind deep in the pocket and do not interact with residues near the mouth nor do they expand the pocket like phospholipids. Unexpectedly, two closely related agonists with similar efficacies (GSK8470 and RJW100) exhibit completely different binding modes. The dramatic repositioning is influenced by a differential ability to establish stable face-to-face π-π-stacking with the LRH-1 residue His-390, as well as by a novel polar interaction mediated by the RJW100 hydroxyl group. The differing binding modes result in distinct mechanisms of action for the two agonists. Finally, we identify a network of conserved water molecules near the ligand-binding site that are important for activation by both agonists. This work reveals a previously unappreciated complexity associated with LRH-1 agonist development and offers insights into rational design strategies.


  • Organizational Affiliation

    From the Department of Biochemistry, Emory University School of Medicine, and.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Nuclear receptor subfamily 5 group A member 2242Homo sapiensMutation(s): 0 
Gene Names: NR5A2B1FCPFFTF
UniProt & NIH Common Fund Data Resources
Find proteins for O00482 (Homo sapiens)
Explore O00482 
Go to UniProtKB:  O00482
PHAROS:  O00482
GTEx:  ENSG00000116833 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO00482
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Nuclear receptor coactivator 2B [auth C]15Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for Q15596 (Homo sapiens)
Explore Q15596 
Go to UniProtKB:  Q15596
PHAROS:  Q15596
GTEx:  ENSG00000140396 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ15596
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
71W
Query on 71W

Download Ideal Coordinates CCD File 
C [auth A](1S,3aR,6aR)-5-hexyl-4-phenyl-3a-(1-phenylethenyl)-1,2,3,3a,6,6a-hexahydropentalen-1-ol
C28 H34 O
ZFXMYHPLTQTTFW-NSVAZKTRSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
71W BindingDB:  5SYZ EC50: 398.11 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.93 Å
  • R-Value Free: 0.228 
  • R-Value Work: 0.205 
  • R-Value Observed: 0.206 
  • Space Group: P 43 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 46.312α = 90
b = 46.312β = 90
c = 219.966γ = 90
Software Package:
Software NamePurpose
HKL-2000data scaling
PHENIXrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)United StatesR01DK095750
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)United StatesF31DK111171
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesT32GM008602

Revision History  (Full details and data files)

  • Version 1.0: 2016-10-12
    Type: Initial release
  • Version 1.1: 2016-10-19
    Changes: Database references
  • Version 1.2: 2016-12-14
    Changes: Database references
  • Version 1.3: 2017-09-06
    Changes: Author supporting evidence
  • Version 1.4: 2019-12-25
    Changes: Author supporting evidence
  • Version 1.5: 2023-10-04
    Changes: Data collection, Database references, Refinement description