3G61

Structure of P-glycoprotein Reveals a Molecular Basis for Poly-Specific Drug Binding


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 4.35 Å
  • R-Value Free: 0.356 
  • R-Value Work: 0.308 
  • R-Value Observed: 0.308 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding.

Aller, S.G.Yu, J.Ward, A.Weng, Y.Chittaboina, S.Zhuo, R.Harrell, P.M.Trinh, Y.T.Zhang, Q.Urbatsch, I.L.Chang, G.

(2009) Science 323: 1718-1722

  • DOI: https://doi.org/10.1126/science.1168750
  • Primary Citation of Related Structures:  
    3G5U, 3G60, 3G61

  • PubMed Abstract: 

    P-glycoprotein (P-gp) detoxifies cells by exporting hundreds of chemically unrelated toxins but has been implicated in multidrug resistance (MDR) in the treatment of cancers. Substrate promiscuity is a hallmark of P-gp activity, thus a structural description of poly-specific drug-binding is important for the rational design of anticancer drugs and MDR inhibitors. The x-ray structure of apo P-gp at 3.8 angstroms reveals an internal cavity of approximately 6000 angstroms cubed with a 30 angstrom separation of the two nucleotide-binding domains. Two additional P-gp structures with cyclic peptide inhibitors demonstrate distinct drug-binding sites in the internal cavity capable of stereoselectivity that is based on hydrophobic and aromatic interactions. Apo and drug-bound P-gp structures have portals open to the cytoplasm and the inner leaflet of the lipid bilayer for drug entry. The inward-facing conformation represents an initial stage of the transport cycle that is competent for drug binding.


  • Organizational Affiliation

    Department of Molecular Biology, Scripps Research Institute, 10550 North Torrey Pines Road, CB105, La Jolla, CA 92037, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Multidrug resistance protein 1a
A, B
1,284Mus musculusMutation(s): 0 
Gene Names: Abcb1amCG_1178
Membrane Entity: Yes 
UniProt
Find proteins for P21447 (Mus musculus)
Explore P21447 
Go to UniProtKB:  P21447
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP21447
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
2J8
Query on 2J8

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A],
E [auth B],
F [auth B]
(4S,11S,18S)-4,11,18-tri(propan-2-yl)-6,13,20-triselena-3,10,17,22,23,24-hexaazatetracyclo[17.2.1.1~5,8~.1~12,15~]tetracosa-1(21),5(24),7,12(23),14,19(22)-hexaene-2,9,16-trione
C24 H30 N6 O3 Se3
FWRNUSMIPQTUHH-BZSNNMDCSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 4.35 Å
  • R-Value Free: 0.356 
  • R-Value Work: 0.308 
  • R-Value Observed: 0.308 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 97.742α = 90
b = 114.978β = 90
c = 375.81γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
CNSrefinement
HKL-2000data reduction
HKL-2000data scaling
CNSphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2009-03-24
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2013-11-13
    Changes: Atomic model
  • Version 1.3: 2020-10-21
    Changes: Data collection, Database references, Derived calculations, Structure summary
  • Version 1.4: 2024-02-21
    Changes: Data collection, Database references