2XJ1

Protein kinase Pim-1 in complex with small molecule inibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.13 Å
  • R-Value Free: 0.212 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.178 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Crystallographic Fragment Screen Identifies Cinnamic Acid Derivatives as Starting Points for Potent Pim-1 Inhibitors

Schulz, M.N.Fanghanel, J.Schafer, M.Badock, V.Briem, H.Boemer, U.Nguyen, D.Husemann, M.Hillig, R.C.

(2011) Acta Crystallogr D Biol Crystallogr 67: 156

  • DOI: https://doi.org/10.1107/S0907444910054144
  • Primary Citation of Related Structures:  
    2XIX, 2XIY, 2XIZ, 2XJ0, 2XJ1, 2XJ2

  • PubMed Abstract: 

    A crystallographic fragment screen was carried out to identify starting points for the development of inhibitors of protein kinase Pim-1, a potential target for tumour therapy. All fragment hits identified via soaking in this study turned out to bind to the unusually hydrophobic pocket at the hinge region. The most potent fragments, two cinnamic acid derivatives (with a best IC(50) of 130 µM), additionally form a well defined hydrogen bond. The balance between hydrophobic and polar interactions makes these molecules good starting points for further optimization. Pim-2 inhibitors from a recently reported high-throughput screening campaign also feature a cinnamic acid moiety. Two of these Pim-2 inhibitors were synthesized, their potencies against Pim-1 were determined and their cocrystal structures were elucidated in order to determine to what degree the binding modes identified by fragment screening are conserved in optimized inhibitors. The structures show that the cinnamic acid moieties indeed adopt the same binding mode. Fragment screening thus correctly identified binding modes which are maintained when fragments are grown into larger and higher affinity inhibitors. The high-throughput screening-derived compound (E)-3-{3-[6-(4-aminocyclohexylamino)-pyrazin-2-yl]phenyl}acrylic acid (compound 1) is the most potent inhibitor of the cinnamic acid series for which the three-dimensional binding mode is known (IC(50) = 17 nM, K(d) = 28 nM). The structure reveals the molecular basis for the large gain in potency between the initial fragment hit and this optimized inhibitor.


  • Organizational Affiliation

    Bayer Schering Pharma AG, Global Drug Discovery, Berlin, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
PROTO-ONCOGENE SERINE/THREONINE-PROTEIN KINASE PIM-1301Homo sapiensMutation(s): 0 
EC: 2.7.1.37 (PDB Primary Data), 2.7.11.1 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for P11309 (Homo sapiens)
Explore P11309 
Go to UniProtKB:  P11309
PHAROS:  P11309
GTEx:  ENSG00000137193 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP11309
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
XJ1
Query on XJ1

Download Ideal Coordinates CCD File 
B [auth A](2E)-3-(3-{6-[(TRANS-4-AMINOCYCLOHEXYL)AMINO]PYRAZIN-2-YL}PHENYL)PROP-2-ENOIC ACID
C19 H22 N4 O2
GPICQYUBSFLTRN-OIQFLZLASA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
SEP
Query on SEP
A
L-PEPTIDE LINKINGC3 H8 N O6 PSER
Binding Affinity Annotations 
IDSourceBinding Affinity
XJ1 PDBBind:  2XJ1 Kd: 28 (nM) from 1 assay(s)
Binding MOAD:  2XJ1 Kd: 28 (nM) from 1 assay(s)
BindingDB:  2XJ1 IC50: 13 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.13 Å
  • R-Value Free: 0.212 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.178 
  • Space Group: P 65
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 95.75α = 90
b = 95.75β = 90
c = 80.932γ = 120
Software Package:
Software NamePurpose
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: 2011-02-23
    Type: Initial release
  • Version 1.1: 2011-05-08
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance