4QP3

Crystal Structure of ERK2 in complex with (S)-2-((9H-purin-6-yl)amino)-3-phenylpropan-1-ol


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.268 
  • R-Value Work: 0.221 
  • R-Value Observed: 0.224 

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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Fragment-based discovery of potent ERK2 pyrrolopyrazine inhibitors.

Burdick, D.J.Wang, S.Heise, C.Pan, B.Drummond, J.Yin, J.Goeser, L.Magnuson, S.Blaney, J.Moffat, J.Wang, W.Chen, H.

(2015) Bioorg Med Chem Lett 25: 4728-4732

  • DOI: https://doi.org/10.1016/j.bmcl.2015.08.048
  • Primary Citation of Related Structures:  
    4QP1, 4QP2, 4QP3, 4QP4, 4QP6, 4QP7, 4QP8, 4QP9, 4QPA

  • PubMed Abstract: 

    A fragment-based lead discovery approach was used to discover novel ERK2 inhibitors. The crystal structure of N-benzyl-9H-purin-6-amine 1 in complex with ERK2 elucidated its hinge-binding mode. In addition, the simultaneous binding of an imidazole molecule adjacent to 1 suggested a direction for fragment expansion. Structure-based core hopping applied to 1 led to 5H-pyrrolo[3,2-b]pyrazine (3) that afforded direct vectors to probe the pockets of interest while retaining the essential hinge binding elements. Utilizing the new vectors for SAR exploration, the new core 3 was quickly optimized to compound 39 resulting in a greater than 6600-fold improvement in potency.


  • Organizational Affiliation

    Department of Discovery Chemistry, Genentech, Inc., South San Francisco, CA 94080, United States. Electronic address: burdick.dan@gene.com.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Mitogen-activated protein kinase 1
A, B
369Homo sapiensMutation(s): 0 
Gene Names: MAPK1ERK2PRKM1PRKM2
EC: 2.7.11.24
UniProt & NIH Common Fund Data Resources
Find proteins for P28482 (Homo sapiens)
Explore P28482 
Go to UniProtKB:  P28482
PHAROS:  P28482
GTEx:  ENSG00000100030 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP28482
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
36Q
Query on 36Q

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
(2S)-3-phenyl-2-(9H-purin-6-ylamino)propan-1-ol
C14 H15 N5 O
KOHQRNQTKFJUQF-NSHDSACASA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
NEP
Query on NEP
A, B
L-PEPTIDE LINKINGC6 H10 N3 O5 PHIS
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.268 
  • R-Value Work: 0.221 
  • R-Value Observed: 0.224 
  • Space Group: P 41 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 83.083α = 90
b = 83.083β = 90
c = 277.013γ = 90
Software Package:
Software NamePurpose
BOSdata collection
PHASERphasing
PHENIXrefinement
DENZOdata reduction
SCALEPACKdata 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: 2015-09-23
    Type: Initial release
  • Version 1.1: 2015-12-16
    Changes: Database references