1OZ1

P38 MITOGEN-ACTIVATED KINASE IN COMPLEX WITH 4-AZAINDOLE INHIBITOR


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.251 
  • R-Value Work: 0.201 
  • R-Value Observed: 0.204 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Design and synthesis of 4-azaindoles as inhibitors of p38 MAP kinase.

Trejo, A.Arzeno, H.Browner, M.Chanda, S.Cheng, S.Comer, D.D.Dalrymple, S.A.Dunten, P.Lafargue, J.Lovejoy, B.Freire-Moar, J.Lim, J.Mcintosh, J.Miller, J.Papp, E.Reuter, D.Roberts, R.Sanpablo, F.Saunders, J.Song, K.Villasenor, A.Warren, S.D.Welch, M.Weller, P.Whiteley, P.E.Zeng, L.Goldstein, D.M.

(2003) J Med Chem 46: 4702-4713

  • DOI: https://doi.org/10.1021/jm0301787
  • Primary Citation of Related Structures:  
    1OZ1

  • PubMed Abstract: 

    Inhibition of the biosynthesis of proinflammatory cytokines such as tumor necrosis factor and interleukin-1 via p38 has been an approach toward the development of a disease modifying agent for the treatment of chronic inflammation and autoimmune diseases. The development of a new core structure of p38 inhibitors, 3-(4-fluorophenyl)-2-(pyridin-4-yl)-1H-pyrrolo[3,2-b] pyridine, is described. X-ray crystallographic data of the lead bound to the active site of p38 was used to guide the optimization of the series. Specific focus was placed on modulating the physical properties of the core while maintaining potent inhibition of p38. These efforts identified 42c as a potent inhibitor of p38, which also possessed the required physical properties worthy of advanced studies.


  • Organizational Affiliation

    Department of Medicinal Chemistry, Roche Palo Alto LLC, 3431 Hillview Avenue, R6-201, Palo Alto, California 94304, USA. alejandro.trejo@roche.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Mitogen-activated protein kinase 14372Homo sapiensMutation(s): 0 
Gene Names: MAPK14 OR CSBP1 OR CSBP2 OR CSBP OR MXI2
EC: 2.7.1.37
UniProt & NIH Common Fund Data Resources
Find proteins for Q16539 (Homo sapiens)
Explore Q16539 
Go to UniProtKB:  Q16539
PHAROS:  Q16539
GTEx:  ENSG00000112062 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ16539
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
FPH
Query on FPH

Download Ideal Coordinates CCD File 
B [auth A]3-(4-FLUOROPHENYL)-2-PYRIDIN-4-YL-1H-PYRROLO[3,2-B]PYRIDIN-1-OL
C18 H12 F N3 O
ZSMYZLKEZDYVPI-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
FPH Binding MOAD:  1OZ1 IC50: 6.5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.251 
  • R-Value Work: 0.201 
  • R-Value Observed: 0.204 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 45.405α = 90
b = 85.454β = 90
c = 125.841γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
DENZOdata reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2003-09-23
    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: 2024-02-14
    Changes: Data collection, Database references, Derived calculations