3HLL

Crystal Structure of Human p38alpha complexed with PH-797804


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.254 
  • R-Value Work: 0.217 
  • R-Value Observed: 0.219 

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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Structural bioinformatics-based prediction of exceptional selectivity of p38 MAP kinase inhibitor PH-797804.

Xing, L.Shieh, H.S.Selness, S.R.Devraj, R.V.Walker, J.K.Devadas, B.Hope, H.R.Compton, R.P.Schindler, J.F.Hirsch, J.L.Benson, A.G.Kurumbail, R.G.Stegeman, R.A.Williams, J.M.Broadus, R.M.Walden, Z.Monahan, J.B.

(2009) Biochemistry 48: 6402-6411

  • DOI: https://doi.org/10.1021/bi900655f
  • Primary Citation of Related Structures:  
    3HL7, 3HLL

  • PubMed Abstract: 

    PH-797804 is a diarylpyridinone inhibitor of p38alpha mitogen-activated protein (MAP) kinase derived from a racemic mixture as the more potent atropisomer (aS), first proposed by molecular modeling and subsequently confirmed by experiments. On the basis of structural comparison with a different biaryl pyrazole template and supported by dozens of high-resolution crystal structures of p38alpha inhibitor complexes, PH-797804 is predicted to possess a high level of specificity across the broad human kinase genome. We used a structural bioinformatics approach to identify two selectivity elements encoded by the TXXXG sequence motif on the p38alpha kinase hinge: (i) Thr106 that serves as the gatekeeper to the buried hydrophobic pocket occupied by 2,4-difluorophenyl of PH-797804 and (ii) the bidentate hydrogen bonds formed by the pyridinone moiety with the kinase hinge requiring an induced 180 degrees rotation of the Met109-Gly110 peptide bond. The peptide flip occurs in p38alpha kinase due to the critical glycine residue marked by its conformational flexibility. Kinome-wide sequence mining revealed rare presentation of the selectivity motif. Corroboratively, PH-797804 exhibited exceptionally high specificity against MAP kinases and the related kinases. No cross-reactivity was observed in large panels of kinase screens (selectivity ratio of >500-fold). In cellular assays, PH-797804 demonstrated superior potency and selectivity consistent with the biochemical measurements. PH-797804 has met safety criteria in human phase I studies and is under clinical development for several inflammatory conditions. Understanding the rationale for selectivity at the molecular level helps elucidate the biological function and design of specific p38alpha kinase inhibitors.


  • Organizational Affiliation

    Structural and Computational Chemistry, St. Louis Laboratories,Pfizer Global Research and Development, 700 Chesterfield Parkway West, Chesterfield, Missouri 63017, USA. li.xing@pfizer.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Mitogen-activated protein kinase 14360Homo sapiensMutation(s): 0 
Gene Names: CSBPCSBP1CSBP2CSPB1MAPK14MXI2THP-1
EC: 2.7.11.24
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 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
I45
Query on I45

Download Ideal Coordinates CCD File 
B [auth A]3-{3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl}-N,4-dimethylbenzamide
C22 H19 Br F2 N2 O3
KCAJXIDMCNPGHZ-UHFFFAOYSA-N
I46
Query on I46

Download Ideal Coordinates CCD File 
C [auth A]2-fluoro-4-[4-(4-fluorophenyl)-1H-pyrazol-3-yl]pyridine
C14 H9 F2 N3
YJCHZVXSPFPKMX-UHFFFAOYSA-N
PO2
Query on PO2

Download Ideal Coordinates CCD File 
D [auth A]HYPOPHOSPHITE
O2 P
GQZXNSPRSGFJLY-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
I45 BindingDB:  3HLL Ki: min: 2.9, max: 5.8 (nM) from 2 assay(s)
Kd: min: 2.5, max: 2.8 (nM) from 2 assay(s)
IC50: min: 1.1, max: 247 (nM) from 6 assay(s)
Binding MOAD:  3HLL Ki: 5.8 (nM) from 1 assay(s)
PDBBind:  3HLL Ki: 5.8 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.254 
  • R-Value Work: 0.217 
  • R-Value Observed: 0.219 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 65.114α = 90
b = 74.645β = 90
c = 77.066γ = 90
Software Package:
Software NamePurpose
ADSCdata collection
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling
REFMACphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2009-07-14
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Advisory, Version format compliance