4AOF

Selective small molecule inhibitor discovered by chemoproteomic assay platform reveals regulation of Th17 cell differentiation by PI3Kgamma

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.30 Å
  • R-Value Free: 0.346 
  • R-Value Work: 0.236 
  • R-Value Observed: 0.242 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history. 


Literature

A Selective Inhibitor Reveals Pi3Kgamma Dependence of T(H)17 Cell Differentiation.

Bergamini, G., Bell, K., Shimamura, S., Werner, T., Cansfield, A., Muller, K., Perrin, J., Rau, C., Ellard, K., Hopf, C., Doce, C., Leggate, D., Mangano, R., Mathieson, T., O'Mahony, A., Plavec, I., Rharbaoui, F., Reinhard, F., Savitski, M.M., Ramsden, N., Hirsch, E., Drewes, G., Rausch, O., Bantscheff, M., Neubauer, G.

(2012) Nat Chem Biol 8: 576

  • DOI: https://doi.org/10.1038/nchembio.957
  • Primary Citation of Related Structures:  
    4AOF

  • PubMed Abstract: 

    We devised a high-throughput chemoproteomics method that enabled multiplexed screening of 16,000 compounds against native protein and lipid kinases in cell extracts. Optimization of one chemical series resulted in CZC24832, which is to our knowledge the first selective inhibitor of phosphoinositide 3-kinase γ (PI3Kγ) with efficacy in in vitro and in vivo models of inflammation. Extensive target- and cell-based profiling of CZC24832 revealed regulation of interleukin-17-producing T helper cell (T(H)17) differentiation by PI3Kγ, thus reinforcing selective inhibition of PI3Kγ as a potential treatment for inflammatory and autoimmune diseases.

    • Organizational Affiliation: 

    Cellzome AG, Heidelberg, Germany.


Macromolecules
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
PHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT GAMMA ISOFORM960Homo sapiensMutation(s): 0 
EC: 2.7.1.153 (PDB Primary Data), 2.7.11.1 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for P48736 (Homo sapiens)
Explore P48736 
Go to UniProtKB:  P48736
PHAROS:  P48736
GTEx:  ENSG00000105851 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP48736
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
7L0
Query on 7L0
Download Ideal Coordinates CCD File 
B [auth A]N-[6-(5-methylsulfonylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]ethanamide
C14 H13 N5 O3 S
RCRCKEODQLBHAY-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
7L0 BindingDB:  4AOF IC50: min: 79.43, max: 6.31e+4 (nM) from 3 assay(s)
PDBBind:  4AOF IC50: 80 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.30 Å
  • R-Value Free: 0.346 
  • R-Value Work: 0.236 
  • R-Value Observed: 0.242 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 142.771α = 90
b = 68.047β = 94.61
c = 109.873γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-05-09
    Type: Initial release
  • Version 1.1: 2012-05-30
    Changes: Other
  • Version 1.2: 2012-07-11
    Changes: Other
  • Version 1.3: 2023-12-20
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description