5AK0

Human PFKFB3 in complex with an indole inhibitor 6


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.03 Å
  • R-Value Free: 0.204 
  • R-Value Work: 0.179 
  • R-Value Observed: 0.181 

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 Potent and Selective Inhibitors of the Metabolic Kinase Pfkfb3.

Boyd, S.Brookfield, J.L.Critchlow, S.E.Cumming, I.A.Curtis, N.J.Debreczeni, J.Degorce, S.L.Donald, C.Evans, N.J.Groombridge, S.Hopcroft, P.Jones, N.P.Kettle, J.G.Lamont, S.Lewis, H.J.Macfaull, P.Mcloughlin, S.B.Rigoreau, L.J.M.Smith, J.M.St-Gallay, S.Stock, J.K.Turnbull, A.P.Wheatley, E.R.Winter, J.Wingfield, J.

(2015) J Med Chem 58: 3611

  • DOI: https://doi.org/10.1021/acs.jmedchem.5b00352
  • Primary Citation of Related Structures:  
    5AJV, 5AJW, 5AJX, 5AJY, 5AJZ, 5AK0

  • PubMed Abstract: 

    A weak screening hit with suboptimal physicochemical properties was optimized against PFKFB3 kinase using critical structure-guided insights. The resulting compounds demonstrated high selectivity over related PFKFB isoforms and modulation of the target in a cellular context. A selected example demonstrated exposure in animals following oral dosing. Examples from this series may serve as useful probes to understand the emerging biology of this metabolic target.


  • Organizational Affiliation

    †Oncology Innovative Medicines Unit, AstraZeneca, 35S47 Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
6-PHOSPHOFRUCTO-2-KINASE/FRUCTOSE-2,6-BISPHOSPHATASE 3520Homo sapiensMutation(s): 0 
EC: 2.7.1.105 (PDB Primary Data), 3.1.3.46 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for Q16875 (Homo sapiens)
Explore Q16875 
Go to UniProtKB:  Q16875
PHAROS:  Q16875
GTEx:  ENSG00000170525 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ16875
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
8V1
Query on 8V1

Download Ideal Coordinates CCD File 
F [auth A](2S)-N-[4-[1-METHYL-3-(1-METHYLPYRAZOL-4-YL)INDOL-5-YL]OXYPHENYL]PYRROLIDINE-2-CARBOXAMIDE
C24 H25 N5 O2
JTIOFEOXCFFWJI-QFIPXVFZSA-N
F6P
Query on F6P

Download Ideal Coordinates CCD File 
E [auth A]6-O-phosphono-beta-D-fructofuranose
C6 H13 O9 P
BGWGXPAPYGQALX-ARQDHWQXSA-N
PO4
Query on PO4

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A]
PHOSPHATE ION
O4 P
NBIIXXVUZAFLBC-UHFFFAOYSA-K
PHS
Query on PHS

Download Ideal Coordinates CCD File 
B [auth A]PHOSPHONIC ACID
H3 O3 P
ABLZXFCXXLZCGV-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.03 Å
  • R-Value Free: 0.204 
  • R-Value Work: 0.179 
  • R-Value Observed: 0.181 
  • Space Group: P 65 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 103.42α = 90
b = 103.42β = 90
c = 260.71γ = 120
Software Package:
Software NamePurpose
BUSTERrefinement
XDSdata reduction
SCALAdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2015-04-22
    Type: Initial release
  • Version 1.1: 2015-05-13
    Changes: Database references
  • Version 1.2: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Data collection, Derived calculations, Other, Structure summary
  • Version 1.3: 2024-05-08
    Changes: Data collection, Database references, Structure summary