1PW6

Low Micromolar Small Molecule Inhibitor of IL-2


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.292 
  • R-Value Work: 0.258 
  • R-Value Observed: 0.259 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Potent small-molecule binding to a dynamic hot spot on IL-2.

Thanos, C.D.Randal, M.Wells, J.A.

(2003) J Am Chem Soc 125: 15280-15281

  • DOI: https://doi.org/10.1021/ja0382617
  • Primary Citation of Related Structures:  
    1PW6, 1PY2

  • PubMed Abstract: 

    The complexes between IL-2 and two similar small molecules, one a lead compound and the other a potent, affinity-optimized compound, were determined by X-ray crystallography. The lead compound (IC50 = 6 muM) bound to a hot spot on IL-2 in a groove that is not apparent in either the unliganded protein or a complex between IL-2 and a weakly bound drug fragment. The affinity-optimized compound (IC50 = 0.06 muM), which has an added aromatic acid fragment, bound in the same groove as the lead compound. In addition, a novel binding site was formed for the aromatic acid which is unseen in the complex with the lead compound. Thus, the hot spot on IL-2 is highly dynamic, with the protein changing form at multiple sites to maximize packing for each compound. Binding-site rigidity is often thought to play a role in high-affinity interactions. However, in this case, specific contacts between the small molecule and the protein are made despite the adaptivity of the hot spot. Given the change in morphology that was observed in IL-2, it is unlikely that a potent inhibitor could have been found by rational design. Therefore, fragment assembly methods offer the stochastic advantage of finding fragments in flexible protein regions where structural changes are unpredictable.


  • Organizational Affiliation

    Sunesis Pharmaceuticals, Inc., 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
Interleukin-2
A, B
133Homo sapiensMutation(s): 0 
Gene Names: IL2
UniProt & NIH Common Fund Data Resources
Find proteins for P60568 (Homo sapiens)
Explore P60568 
Go to UniProtKB:  P60568
PHAROS:  P60568
GTEx:  ENSG00000109471 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP60568
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
FRB
Query on FRB

Download Ideal Coordinates CCD File 
D [auth A],
E [auth B]
2-CYCLOHEXYL-N-(2-{4-[5-(2,3-DICHLORO-PHENYL)-2H-PYRAZOL-3-YL]-PIPERIDIN-1-YL}-2-OXO-ETHYL)-2-GUANIDINO-ACETAMIDE
C25 H33 Cl2 N7 O2
SSSXBBASYYVGCI-HSZRJFAPSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
C [auth A]SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Binding Affinity Annotations 
IDSourceBinding Affinity
FRB BindingDB:  1PW6 Kd: 55 (nM) from 1 assay(s)
PDBBind:  1PW6 IC50: 6000 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.292 
  • R-Value Work: 0.258 
  • R-Value Observed: 0.259 
  • Space Group: P 41 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 79.889α = 90
b = 79.889β = 90
c = 171.891γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
d*TREKdata scaling
AMoREphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2004-01-13
    Type: Initial release
  • Version 1.1: 2008-04-29
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2017-10-11
    Changes: Refinement description
  • Version 1.4: 2018-02-14
    Changes: Experimental preparation