3KAG

Structure-guided design of alpha-amino acid-derived Pin1 inhibitors


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.255 
  • R-Value Work: 0.202 
  • R-Value Observed: 0.205 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Structure-guided design of alpha-amino acid-derived Pin1 inhibitors

Potter, A.J.Ray, S.Gueritz, L.Nunns, C.L.Bryant, C.J.Scrace, S.F.Matassova, N.Baker, L.M.Dokurno, P.Robinson, D.A.Surgenor, A.E.Davis, B.Murray, J.B.Richardson, C.M.Moore, J.D.

(2010) Bioorg Med Chem Lett 20: 586-590

  • DOI: https://doi.org/10.1016/j.bmcl.2009.11.090
  • Primary Citation of Related Structures:  
    3KAB, 3KAC, 3KAD, 3KAF, 3KAG, 3KAH, 3KAI, 3KCE

  • PubMed Abstract: 

    The peptidyl prolyl cis/trans isomerase Pin1 is a promising molecular target for anti-cancer therapeutics. Here we report the structure-guided evolution of an indole 2-carboxylic acid fragment hit into a series of alpha-benzimidazolyl-substituted amino acids. Examples inhibited Pin1 activity with IC(50) <100nM, but were inactive on cells. Replacement of the benzimidazole ring with a naphthyl group resulted in a 10-50-fold loss in ligand potency, but these examples downregulated biomarkers of Pin1 activity and blocked proliferation of PC3 cells.


  • Organizational Affiliation

    Vernalis (R&D) Ltd, Granta Park, Great Abington, Cambridge CB21 6GB, United Kingdom.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1167Homo sapiensMutation(s): 1 
Gene Names: PIN1
EC: 5.2.1.8
UniProt & NIH Common Fund Data Resources
Find proteins for Q13526 (Homo sapiens)
Explore Q13526 
Go to UniProtKB:  Q13526
PHAROS:  Q13526
GTEx:  ENSG00000127445 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ13526
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
12P
Query on 12P

Download Ideal Coordinates CCD File 
C [auth A]DODECAETHYLENE GLYCOL
C24 H50 O13
WRZXKWFJEFFURH-UHFFFAOYSA-N
4D7
Query on 4D7

Download Ideal Coordinates CCD File 
B [auth A]3-(1H-benzimidazol-2-yl)-N-[(2-methylfuran-3-yl)carbonyl]-D-alanine
C16 H15 N3 O4
IBXZTXVMQARJHH-CYBMUJFWSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
4D7 PDBBind:  3KAG IC50: 6600 (nM) from 1 assay(s)
BindingDB:  3KAG IC50: 6600 (nM) from 1 assay(s)
Binding MOAD:  3KAG IC50: 6600 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.255 
  • R-Value Work: 0.202 
  • R-Value Observed: 0.205 
  • Space Group: P 31 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 68.504α = 90
b = 68.504β = 90
c = 79.56γ = 120
Software Package:
Software NamePurpose
CrystalCleardata collection
AMoREphasing
REFMACrefinement
d*TREKdata reduction
d*TREKdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2009-12-22
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2021-11-10
    Changes: Database references, Derived calculations
  • Version 1.3: 2023-11-01
    Changes: Data collection, Refinement description