4KS8

PAK6 kinase domain in complex with sunitinib


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.261 
  • R-Value Work: 0.218 
  • R-Value Observed: 0.220 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Substrate and Inhibitor Specificity of the Type II p21-Activated Kinase, PAK6.

Gao, J.Ha, B.H.Lou, H.J.Morse, E.M.Zhang, R.Calderwood, D.A.Turk, B.E.Boggon, T.J.

(2013) PLoS One 8: e77818-e77818

  • DOI: https://doi.org/10.1371/journal.pone.0077818
  • Primary Citation of Related Structures:  
    4KS7, 4KS8

  • PubMed Abstract: 

    The p21-activated kinases (PAKs) are important effectors of Rho-family small GTPases. The PAK family consists of two groups, type I and type II, which have different modes of regulation and signaling. PAK6, a type II PAK, influences behavior and locomotor function in mice and has an ascribed role in androgen receptor signaling. Here we show that PAK6 has a peptide substrate specificity very similar to the other type II PAKs, PAK4 and PAK5 (PAK7). We find that PAK6 catalytic activity is inhibited by a peptide corresponding to its N-terminal pseudosubstrate. Introduction of a melanoma-associated mutation, P52L, into this peptide reduces pseudosubstrate autoinhibition of PAK6, and increases phosphorylation of its substrate PACSIN1 (Syndapin I) in cells. Finally we determine two co-crystal structures of PAK6 catalytic domain in complex with ATP-competitive inhibitors. We determined the 1.4 Å co-crystal structure of PAK6 with the type II PAK inhibitor PF-3758309, and the 1.95 Å co-crystal structure of PAK6 with sunitinib. These findings provide new insights into the structure-function relationships of PAK6 and may facilitate development of PAK6 targeted therapies.


  • Organizational Affiliation

    State Key Laboratory for Conservation and Utilization of Subtropical Agro-biosciences, The Key Laboratory of Ministry of Education for Microbial and Plant Genetic Engineering, and College of Life Science and Technology, Guangxi University, Nanning, Guangxi, China ; Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, United States of America.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Serine/threonine-protein kinase PAK 6292Homo sapiensMutation(s): 0 
Gene Names: PAK6PAK5
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for Q9NQU5 (Homo sapiens)
Explore Q9NQU5 
Go to UniProtKB:  Q9NQU5
PHAROS:  Q9NQU5
GTEx:  ENSG00000137843 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9NQU5
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
B49
Query on B49

Download Ideal Coordinates CCD File 
B [auth A]N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carbo xamide
C22 H27 F N4 O2
WINHZLLDWRZWRT-ATVHPVEESA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
SEP
Query on SEP
A
L-PEPTIDE LINKINGC3 H8 N O6 PSER
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.261 
  • R-Value Work: 0.218 
  • R-Value Observed: 0.220 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 49.616α = 90
b = 60.099β = 90
c = 99.979γ = 90
Software Package:
Software NamePurpose
ADSCdata collection
PHASERphasing
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-09-11
    Type: Initial release
  • Version 1.1: 2013-11-06
    Changes: Database references
  • Version 1.2: 2013-12-04
    Changes: Database references
  • Version 1.3: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description, Structure summary
  • Version 1.4: 2024-10-09
    Changes: Structure summary