2AXN

Crystal structure of the human inducible form 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.233 
  • R-Value Work: 0.209 
  • R-Value Observed: 0.209 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Crystal structure of the hypoxia-inducible form of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3): a possible new target for cancer therapy.

Kim, S.G.Manes, N.P.El-Maghrabi, M.R.Lee, Y.H.

(2006) J Biol Chem 281: 2939-2944

  • DOI: https://doi.org/10.1074/jbc.M511019200
  • Primary Citation of Related Structures:  
    2AXN

  • PubMed Abstract: 

    The hypoxia-inducible form of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3) plays a crucial role in the progression of cancerous cells by enabling their glycolytic pathways even under severe hypoxic conditions. To understand its structural architecture and to provide a molecular scaffold for the design of new cancer therapeutics, the crystal structure of the human form was determined. The structure at 2.1 A resolution shows that the overall folding and functional dimerization are very similar to those of the liver (PFKFB1) and testis (PFKFB4) forms, as expected from sequence homology. However, in this structure, the N-terminal regulatory domain is revealed for the first time among the PFKFB isoforms. With a beta-hairpin structure, the N terminus interacts with the 2-Pase domain to secure binding of fructose-6-phosphate to the active pocket, slowing down the release of fructose-6-phosphate from the phosphoenzyme intermediate product complex. The C-terminal regulatory domain is mostly disordered, leaving the active pocket of the fructose-2,6-bisphosphatase domain wide open. The active pocket of the 6-phosphofructo-2-kinase domain has a more rigid conformation, allowing independent bindings of substrates, fructose-6-phosphate and ATP, with higher affinities than other isoforms. Intriguingly, the structure shows an EDTA molecule bound to the fructose-6-phosphate site of the 6-phosphofructo-2-kinase active pocket despite its unfavorable liganding concentration, suggesting a high affinity. EDTA is not removable from the site with fructose-6-P alone but is with both ATP and fructose-6-P or with fructose-2,6-bisphosphate. This finding suggests that a molecule in which EDTA is covalently linked to ADP is a good starting molecule for the development of new cancer-therapeutic molecules.


  • Organizational Affiliation

    Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana 70803, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (6PF-2-K/Fru- 2,6-P2ASE brain/placenta-type isozyme) (iPFK-2) [Includes: 6- phosphofructo-2-kinase (EC 2.7.1.105); Fructose-2,6-bisphosphatase (EC 3.1.3.46)]520Homo sapiensMutation(s): 0 
Gene Names: PFKFB3
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
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  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
ADP
Query on ADP

Download Ideal Coordinates CCD File 
D [auth A]ADENOSINE-5'-DIPHOSPHATE
C10 H15 N5 O10 P2
XTWYTFMLZFPYCI-KQYNXXCUSA-N
EDT
Query on EDT

Download Ideal Coordinates CCD File 
C [auth A]{[-(BIS-CARBOXYMETHYL-AMINO)-ETHYL]-CARBOXYMETHYL-AMINO}-ACETIC ACID
C10 H16 N2 O8
KCXVZYZYPLLWCC-UHFFFAOYSA-N
F6P
Query on F6P

Download Ideal Coordinates CCD File 
B [auth A]6-O-phosphono-beta-D-fructofuranose
C6 H13 O9 P
BGWGXPAPYGQALX-ARQDHWQXSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.233 
  • R-Value Work: 0.209 
  • R-Value Observed: 0.209 
  • Space Group: P 65 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 102.58α = 90
b = 102.58β = 90
c = 259.84γ = 120
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
CNSrefinement

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2005-12-06
    Type: Initial release
  • Version 1.1: 2008-05-01
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Data collection, Derived calculations, Structure summary
  • Version 1.4: 2023-08-23
    Changes: Data collection, Database references, Refinement description, Structure summary