2X4Z

Crystal Structure of the Human p21-Activated Kinase 4 in Complex with PF-03758309


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.262 
  • R-Value Work: 0.200 
  • R-Value Observed: 0.200 

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Ligand Structure Quality Assessment 


This is version 2.0 of the entry. See complete history


Literature

Small-Molecule P21-Activated Kinase Inhibitor Pf- 3758309 is a Potent Inhibitor of Oncogenic Signaling and Tumor Growth.

Murray, B.Guo, C.Piraino, J.Westwick, J.Zhang, C.Lamerdin, J.Dagostino, E.Knighton, D.R.Loi, C.-M.Zager, M.Kraynov, E.Popoff, I.Christensen, J.Martinez, R.Kephart, S.Marakovits, J.Karlicek, S.Bergqvist, S.Smeal, T.

(2010) Proc Natl Acad Sci U S A 107: 9446

  • DOI: https://doi.org/10.1073/pnas.0911863107
  • Primary Citation of Related Structures:  
    2X4Z

  • PubMed Abstract: 

    Despite abundant evidence that aberrant Rho-family GTPase activation contributes to most steps of cancer initiation and progression, there is a dearth of inhibitors of their effectors (e.g., p21-activated kinases). Through high-throughput screening and structure-based design, we identify PF-3758309, a potent (K(d) = 2.7 nM), ATP-competitive, pyrrolopyrazole inhibitor of PAK4. In cells, PF-3758309 inhibits phosphorylation of the PAK4 substrate GEF-H1 (IC(50) = 1.3 nM) and anchorage-independent growth of a panel of tumor cell lines (IC(50) = 4.7 +/- 3 nM). The molecular underpinnings of PF-3758309 biological effects were characterized using an integration of traditional and emerging technologies. Crystallographic characterization of the PF-3758309/PAK4 complex defined determinants of potency and kinase selectivity. Global high-content cellular analysis confirms that PF-3758309 modulates known PAK4-dependent signaling nodes and identifies unexpected links to additional pathways (e.g., p53). In tumor models, PF-3758309 inhibits PAK4-dependent pathways in proteomic studies and regulates functional activities related to cell proliferation and survival. PF-3758309 blocks the growth of multiple human tumor xenografts, with a plasma EC(50) value of 0.4 nM in the most sensitive model. This study defines PAK4-related pathways, provides additional support for PAK4 as a therapeutic target with a unique combination of functions (apoptotic, cytoskeletal, cell-cycle), and identifies a potent, orally available small-molecule PAK inhibitor with significant promise for the treatment of human cancers.


  • Organizational Affiliation

    Pfizer Oncology, Pfizer, San Diego, CA 92121, USA. brion.murray@pfizer.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
SERINE/THREONINE-PROTEIN KINASE PAK 4296Homo sapiensMutation(s): 4 
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for O96013 (Homo sapiens)
Explore O96013 
Go to UniProtKB:  O96013
PHAROS:  O96013
GTEx:  ENSG00000130669 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO96013
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
SEP
Query on SEP
A
L-PEPTIDE LINKINGC3 H8 N O6 PSER
Binding Affinity Annotations 
IDSourceBinding Affinity
7KC BindingDB:  2X4Z Ki: 15 (nM) from 1 assay(s)
IC50: min: 18, max: 19 (nM) from 2 assay(s)
Binding MOAD:  2X4Z Kd: 2.7 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.262 
  • R-Value Work: 0.200 
  • R-Value Observed: 0.200 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 55.654α = 90
b = 65.923β = 90
c = 84.653γ = 90
Software Package:
Software NamePurpose
CNSrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2010-05-19
    Type: Initial release
  • Version 1.1: 2011-05-07
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 2.0: 2019-01-23
    Changes: Atomic model, Data collection, Derived calculations, Non-polymer description, Other, Structure summary