4TYO

PPIase in complex with a non-phosphate small molecule inhibitor.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.75 Å
  • R-Value Free: 0.211 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.188 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Structure-based design of novel human Pin1 inhibitors (III): Optimizing affinity beyond the phosphate recognition pocket.

Guo, C.Hou, X.Dong, L.Marakovits, J.Greasley, S.Dagostino, E.Ferre, R.Catherine Johnson, M.Humphries, P.S.Li, H.Paderes, G.D.Piraino, J.Kraynov, E.Murray, B.W.

(2014) Bioorg Med Chem Lett 24: 4187-4191

  • DOI: https://doi.org/10.1016/j.bmcl.2014.07.044
  • Primary Citation of Related Structures:  
    4TYO

  • PubMed Abstract: 

    The design of potent Pin1 inhibitors has been challenging because its active site specifically recognizes a phospho-protein epitope. The de novo design of phosphate-based Pin1 inhibitors focusing on the phosphate recognition pocket and the successful replacement of the phosphate group with a carboxylate have been previously reported. The potency of the carboxylate series is now further improved through structure-based optimization of ligand-protein interactions in the proline binding site which exploits the H-bond interactions necessary for Pin1 catalytic function. Further optimization using a focused library approach led to the discovery of low nanomolar non-phosphate small molecular Pin1 inhibitors. Structural modifications designed to improve cell permeability resulted in Pin1 inhibitors with low micromolar anti-proliferative activities against cancer cells.


  • Organizational Affiliation

    Oncology Medicinal Chemistry, Pfizer Worldwide Research & Development, San Diego, CA 92121, USA. Electronic address: alexguo01@gmail.com.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1
A, B
123Homo sapiensMutation(s): 2 
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
Binding Affinity Annotations 
IDSourceBinding Affinity
39X Binding MOAD:  4TYO Ki: 80 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.75 Å
  • R-Value Free: 0.211 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.188 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 117.559α = 90
b = 36.525β = 100.82
c = 51.251γ = 90
Software Package:
Software NamePurpose
SCALEPACKdata scaling
BUSTER-TNTrefinement
PDB_EXTRACTdata extraction
BUSTERrefinement

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-08-20
    Type: Initial release
  • Version 1.1: 2014-10-01
    Changes: Database references
  • Version 1.2: 2017-11-22
    Changes: Database references, Derived calculations, Other, Refinement description, Source and taxonomy
  • Version 1.3: 2023-12-27
    Changes: Data collection, Database references, Refinement description