3QKD

Crystal structure of Bcl-xL in complex with a Quinazoline sulfonamide inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.02 Å
  • R-Value Free: 0.231 
  • R-Value Work: 0.192 
  • R-Value Observed: 0.194 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Quinazoline sulfonamides as dual binders of the proteins B-cell lymphoma 2 and B-cell lymphoma extra long with potent proapoptotic cell-based activity.

Sleebs, B.E.Czabotar, P.E.Fairbrother, W.J.Fairlie, W.D.Flygare, J.A.Huang, D.C.Kersten, W.J.Koehler, M.F.Lessene, G.Lowes, K.Parisot, J.P.Smith, B.J.Smith, M.L.Souers, A.J.Street, I.P.Yang, H.Baell, J.B.

(2011) J Med Chem 54: 1914-1926

  • DOI: https://doi.org/10.1021/jm101596e
  • Primary Citation of Related Structures:  
    3QKD

  • PubMed Abstract: 

    ABT-737 and ABT-263 are potent inhibitors of the BH3 antiapoptotic proteins, Bcl-x(L) and Bcl-2. This class of putative anticancer agents invariantly contains an acylsulfonamide core. We have designed and synthesized a series of novel quinazoline-based inhibitors of Bcl-2 and Bcl-x(L) that contain a heterocyclic alternative to the acylsulfonamide. These compounds exhibit submicromolar, mechanism-based activity in human small-cell lung carcinoma cell lines in the presence of 10% human serum. This comprises the first successful demonstration of a quinazoline sulfonamide core serving as an effective benzoylsulfonamide bioisostere. Additionally, these novel quinazolines comprise only the second known class of Bcl-2 family protein inhibitors to induce mechanism-based cell death.


  • Organizational Affiliation

    The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bcl-2-like protein 1
A, B
181Homo sapiensMutation(s): 0 
Gene Names: BCL2L1BCL2LBCLX
UniProt & NIH Common Fund Data Resources
Find proteins for Q07817 (Homo sapiens)
Explore Q07817 
Go to UniProtKB:  Q07817
PHAROS:  Q07817
GTEx:  ENSG00000171552 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ07817
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
HI0
Query on HI0

Download Ideal Coordinates CCD File 
C [auth A],
F [auth B]
(R)-N-(7-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)quinazolin-4-yl)-4-(4-(dimethylamino)-1-(phenylthio)butan-2-ylamino)-3-nitrobenzenesulfonamide
C43 H45 Cl N8 O4 S2
LLJSSTLCMHGPSB-UUWRZZSWSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
E [auth A]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
D [auth A]CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
HI0 PDBBind:  3QKD Kd: 4.2 (nM) from 1 assay(s)
Binding MOAD:  3QKD IC50: 3 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.02 Å
  • R-Value Free: 0.231 
  • R-Value Work: 0.192 
  • R-Value Observed: 0.194 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 65.598α = 90
b = 74.484β = 90
c = 87.828γ = 90
Software Package:
Software NamePurpose
CrystalCleardata collection
PHASESphasing
REFMACrefinement
HKL-2000data reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2011-04-06
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2023-11-01
    Changes: Data collection, Database references, Derived calculations, Refinement description