2AZ5

Crystal Structure of TNF-alpha with a small molecule inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.278 
  • R-Value Work: 0.220 
  • R-Value Observed: 0.227 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Small-molecule inhibition of TNF-alpha.

He, M.M.Smith, A.S.Oslob, J.D.Flanagan, W.M.Braisted, A.C.Whitty, A.Cancilla, M.T.Wang, J.Lugovskoy, A.A.Yoburn, J.C.Fung, A.D.Farrington, G.Eldredge, J.K.Day, E.S.Cruz, L.A.Cachero, T.G.Miller, S.K.Friedman, J.E.Choong, I.C.Cunningham, B.C.

(2005) Science 310: 1022-1025

  • DOI: https://doi.org/10.1126/science.1116304
  • Primary Citation of Related Structures:  
    2AZ5

  • PubMed Abstract: 

    We have identified a small-molecule inhibitor of tumor necrosis factor alpha (TNF-alpha) that promotes subunit disassembly of this trimeric cytokine family member. The compound inhibits TNF-alpha activity in biochemical and cell-based assays with median inhibitory concentrations of 22 and 4.6 micromolar, respectively. Formation of an intermediate complex between the compound and the intact trimer results in a 600-fold accelerated subunit dissociation rate that leads to trimer dissociation. A structure solved by x-ray crystallography reveals that a single compound molecule displaces a subunit of the trimer to form a complex with a dimer of TNF-alpha subunits.


  • Organizational Affiliation

    Sunesis Pharmaceuticals, Incorporated, 341 Oyster Point Boulevard, South San Francisco, CA 94080, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tumor necrosis factor (TNF-alpha) (Tumor necrosis factor ligand superfamily member 2) (TNF-a) (Cachectin) [Contains: Tumor necrosis factor, membrane form; Tumor necrosis factor, soluble form]
A, B, C, D
148Homo sapiensMutation(s): 0 
Gene Names: TNFTNFATNFSF2
UniProt & NIH Common Fund Data Resources
Find proteins for P01375 (Homo sapiens)
Explore P01375 
Go to UniProtKB:  P01375
PHAROS:  P01375
GTEx:  ENSG00000232810 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP01375
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
307
Query on 307

Download Ideal Coordinates CCD File 
E [auth A],
F [auth C]
6,7-DIMETHYL-3-[(METHYL{2-[METHYL({1-[3-(TRIFLUOROMETHYL)PHENYL]-1H-INDOL-3-YL}METHYL)AMINO]ETHYL}AMINO)METHYL]-4H-CHROMEN-4-ONE
C32 H32 F3 N3 O2
JZNXLPPJRFFECJ-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
307 BindingDB:  2AZ5 Kd: min: 3, max: 1.30e+4 (nM) from 12 assay(s)
IC50: min: 1200, max: 2.20e+4 (nM) from 4 assay(s)
PDBBind:  2AZ5 Kd: 5360 (nM) from 1 assay(s)
Binding MOAD:  2AZ5 IC50: 2.20e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.278 
  • R-Value Work: 0.220 
  • R-Value Observed: 0.227 
  • Space Group: H 3
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 165.254α = 90
b = 165.254β = 90
c = 63.728γ = 120
Software Package:
Software NamePurpose
REFMACrefinement
PDB_EXTRACTdata extraction
MOSFLMdata reduction
CCP4data scaling
AMoREphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2005-11-29 
  • Deposition Author(s): He, M.M.

Revision History  (Full details and data files)

  • Version 1.0: 2005-11-29
    Type: Initial release
  • Version 1.1: 2008-05-01
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2018-02-07
    Changes: Experimental preparation
  • Version 1.4: 2023-08-23
    Changes: Data collection, Database references, Derived calculations, Refinement description