4S0S

STRUCTURE OF HUMAN PREGNANE X RECEPTOR LIGAND BINDING DOMAIN with ADNECTIN-1


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.229 
  • R-Value Work: 0.216 
  • R-Value Observed: 0.217 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Developing Adnectins That Target SRC Co-Activator Binding to PXR: A Structural Approach toward Understanding Promiscuity of PXR.

Khan, J.A.Camac, D.M.Low, S.Tebben, A.J.Wensel, D.L.Wright, M.C.Su, J.Jenny, V.Gupta, R.D.Ruzanov, M.Russo, K.A.Bell, A.An, Y.Bryson, J.W.Gao, M.Gambhire, P.Baldwin, E.T.Gardner, D.Cavallaro, C.L.Duncia, J.V.Hynes, J.

(2015) J Mol Biol 427: 924-942

  • DOI: https://doi.org/10.1016/j.jmb.2014.12.022
  • Primary Citation of Related Structures:  
    4S0S, 4S0T, 4XHD

  • PubMed Abstract: 

    The human pregnane X receptor (PXR) is a promiscuous nuclear receptor that functions as a sensor to a wide variety of xenobiotics and regulates expression of several drug metabolizing enzymes and transporters. We have generated "Adnectins", derived from 10th fibronectin type III domain ((10)Fn3), that target the PXR ligand binding domain (LBD) interactions with the steroid receptor co-activator-1 (SRC-1) peptide, displacing SRC-1 binding. Adnectins are structurally homologous to the immunoglobulin superfamily. Three different co-crystal structures of PXR LBD with Adnectin-1 and CCR1 (CC chemokine receptor-1) antagonist Compound-1 were determined. This structural information was used to modulate PXR affinity for a related CCR1 antagonist compound that entered into clinical trials for rheumatoid arthritis. The structures of PXR with Adnectin-1 reveal specificity of Adnectin-1 in not only targeting the interface of the SRC-1 interactions but also engaging the same set of residues that are involved in binding of SRC-1 to PXR. Substituting SRC-1 with Adnectin-1 does not alter the binding conformation of Compound-1 in the ligand binding pocket. The structure also reveals the possibility of using Adnectins as crystallization chaperones to generate structures of PXR with compounds of interest.


  • Organizational Affiliation

    Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA. Electronic address: javed.khan@bms.com.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Nuclear receptor subfamily 1 group I member 2
A, B
315Homo sapiensMutation(s): 0 
Gene Names: NR1I2PXR
UniProt & NIH Common Fund Data Resources
Find proteins for O75469 (Homo sapiens)
Explore O75469 
Go to UniProtKB:  O75469
PHAROS:  O75469
GTEx:  ENSG00000144852 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO75469
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Adnectin-1C [auth D],
D [auth E]
120Homo sapiensMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
Expand
  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.229 
  • R-Value Work: 0.216 
  • R-Value Observed: 0.217 
  • Space Group: P 4
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 119.234α = 90
b = 119.234β = 90
c = 83.706γ = 90
Software Package:
Software NamePurpose
BUSTER-TNTrefinement
PDB_EXTRACTdata extraction
BUSTERrefinement

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

  • Released Date: 2015-02-11 
  • Deposition Author(s): Khan, J.A.

Revision History  (Full details and data files)

  • Version 1.0: 2015-02-11
    Type: Initial release
  • Version 1.1: 2015-02-25
    Changes: Database references
  • Version 1.2: 2024-02-28
    Changes: Data collection, Database references