4EHR

Crystal structure of Bcl-Xl complex with 4-(5-butyl-3-(hydroxymethyl)-1-phenyl-1h-pyrazol-4-yl)-3-(3,4-dihydro-2(1h)-isoquinolinylcarbonyl)-n-((2-(trimethylsilyl)ethyl)sulfonyl)benzamide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.09 Å
  • R-Value Free: 0.283 
  • R-Value Work: 0.233 
  • R-Value Observed: 0.235 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Pyrazole and pyrimidine phenylacylsulfonamides as dual Bcl-2/Bcl-xL antagonists.

Schroeder, G.M.Wei, D.Banfi, P.Cai, Z.W.Lippy, J.Menichincheri, M.Modugno, M.Naglich, J.Penhallow, B.Perez, H.L.Sack, J.Schmidt, R.J.Tebben, A.Yan, C.Zhang, L.Galvani, A.Lombardo, L.J.Borzilleri, R.M.

(2012) Bioorg Med Chem Lett 22: 3951-3956

  • DOI: https://doi.org/10.1016/j.bmcl.2012.04.106
  • Primary Citation of Related Structures:  
    4EHR

  • PubMed Abstract: 

    5-Butyl-1,4-diphenyl pyrazole and 2-amino-5-chloro pyrimidine acylsulfonamides were developed as potent dual antagonists of Bcl-2 and Bcl-xL. Compounds were optimized for binding to the I88, L92, I95, and F99 pockets normally occupied by pro-apoptotic protein Bim. An X-ray crystal structure confirmed the proposed binding mode. Observation of cytochrome c release from isolated mitochondria in MV-411 cells provides further evidence of target inhibition. Compounds demonstrated submicromolar antiproliferative activity in Bcl-2/Bcl-xL dependent cell lines.


  • Organizational Affiliation

    Bristol-Myers Squibb Research, PO Box 4000, Princeton, NJ 08543-4000, USA. gretchen.schroeder@bms.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bcl-2-like protein 1172Homo 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 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
0Q5
Query on 0Q5

Download Ideal Coordinates CCD File 
B [auth A]4-[5-butyl-3-(hydroxymethyl)-1-phenyl-1H-pyrazol-4-yl]-3-(3,4-dihydroisoquinolin-2(1H)-ylcarbonyl)-N-{[2-(trimethylsilyl)ethyl]sulfonyl}benzamide
C36 H44 N4 O5 S Si
KDMMHDWLRNJPDK-UHFFFAOYSA-N
IMD
Query on IMD

Download Ideal Coordinates CCD File 
C [auth A]IMIDAZOLE
C3 H5 N2
RAXXELZNTBOGNW-UHFFFAOYSA-O
Binding Affinity Annotations 
IDSourceBinding Affinity
0Q5 Binding MOAD:  4EHR IC50: 13 (nM) from 1 assay(s)
PDBBind:  4EHR IC50: 13 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.09 Å
  • R-Value Free: 0.283 
  • R-Value Work: 0.233 
  • R-Value Observed: 0.235 
  • Space Group: P 42 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 102.227α = 90
b = 102.227β = 90
c = 34.929γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2012-06-06
    Type: Initial release
  • Version 1.1: 2012-06-13
    Changes: Database references
  • Version 1.2: 2024-02-28
    Changes: Data collection, Database references, Derived calculations