4OTI

Crystal Structure of PRK1 Catalytic Domain in Complex with Tofacitinib


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.93 Å
  • R-Value Free: 0.226 
  • R-Value Work: 0.185 
  • R-Value Observed: 0.187 

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This is version 1.1 of the entry. See complete history


Literature

Crystal Structures of PRK1 in Complex with the Clinical Compounds Lestaurtinib and Tofacitinib Reveal Ligand Induced Conformational Changes.

Chamberlain, P.Delker, S.Pagarigan, B.Mahmoudi, A.Jackson, P.Abbasian, M.Muir, J.Raheja, N.Cathers, B.

(2014) PLoS One 9: e103638-e103638

  • DOI: https://doi.org/10.1371/journal.pone.0103638
  • Primary Citation of Related Structures:  
    4OTD, 4OTG, 4OTH, 4OTI

  • PubMed Abstract: 

    Protein kinase C related kinase 1 (PRK1) is a component of Rho-GTPase, androgen receptor, histone demethylase and histone deacetylase signaling pathways implicated in prostate and ovarian cancer. Herein we describe the crystal structure of PRK1 in apo form, and also in complex with a panel of literature inhibitors including the clinical candidates lestaurtinib and tofacitinib, as well as the staurosporine analog Ro-31-8220. PRK1 is a member of the AGC-kinase class, and as such exhibits the characteristic regulatory sequence at the C-terminus of the catalytic domain--the 'C-tail'. The C-tail fully encircles the catalytic domain placing a phenylalanine in the ATP-binding site. Our inhibitor structures include examples of molecules which both interact with, and displace the C-tail from the active site. This information may assist in the design of inhibitors targeting both PRK and other members of the AGC kinase family.


  • Organizational Affiliation

    Celgene Corporation, San Diego, California, United States of America; Department of Biochemistry and Structural Biology, Celgene Corporation, San Diego, California, United States of America.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Serine/threonine-protein kinase N1341Homo sapiensMutation(s): 0 
Gene Names: PKN1PAK1PKNPRK1PRKCL1
EC: 2.7.11.13
UniProt & NIH Common Fund Data Resources
Find proteins for Q16512 (Homo sapiens)
Explore Q16512 
Go to UniProtKB:  Q16512
PHAROS:  Q16512
GTEx:  ENSG00000123143 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ16512
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
MI1
Query on MI1

Download Ideal Coordinates CCD File 
B [auth A]3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile
C16 H20 N6 O
UJLAWZDWDVHWOW-YPMHNXCESA-N
Modified Residues  2 Unique
IDChains TypeFormula2D DiagramParent
SEP
Query on SEP
A
L-PEPTIDE LINKINGC3 H8 N O6 PSER
TPO
Query on TPO
A
L-PEPTIDE LINKINGC4 H10 N O6 PTHR
Binding Affinity Annotations 
IDSourceBinding Affinity
MI1 BindingDB:  4OTI Kd: min: 170, max: 200 (nM) from 2 assay(s)
Binding MOAD:  4OTI IC50: 43 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.93 Å
  • R-Value Free: 0.226 
  • R-Value Work: 0.185 
  • R-Value Observed: 0.187 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 56.281α = 90
b = 72.486β = 90
c = 94.481γ = 90
Software Package:
Software NamePurpose
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-08-27
    Type: Initial release
  • Version 1.1: 2018-01-24
    Changes: Structure summary