2QB5

Crystal Structure of Human Inositol 1,3,4-Trisphosphate 5/6-Kinase (ITPK1) in Complex with ADP and Mn2+


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.229 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.183 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Integration of inositol phosphate signaling pathways via human ITPK1.

Chamberlain, P.P.Qian, X.Stiles, A.R.Cho, J.Jones, D.H.Lesley, S.A.Grabau, E.A.Shears, S.B.Spraggon, G.

(2007) J Biol Chem 282: 28117-28125

  • DOI: https://doi.org/10.1074/jbc.M703121200
  • Primary Citation of Related Structures:  
    2Q7D, 2QB5

  • PubMed Abstract: 

    Inositol 1,3,4-trisphosphate 5/6-kinase (ITPK1) is a reversible, poly-specific inositol phosphate kinase that has been implicated as a modifier gene in cystic fibrosis. Upon activation of phospholipase C at the plasma membrane, inositol 1,4,5-trisphosphate enters the cytosol and is inter-converted by an array of kinases and phosphatases into other inositol phosphates with diverse and critical cellular activities. In mammals it has been established that inositol 1,3,4-trisphosphate, produced from inositol 1,4,5-trisphosphate, lies in a branch of the metabolic pathway that is separate from inositol 3,4,5,6-tetrakisphosphate, which inhibits plasma membrane chloride channels. We have determined the molecular mechanism for communication between these two pathways, showing that phosphate is transferred between inositol phosphates via ITPK1-bound nucleotide. Intersubstrate phosphate transfer explains how competing substrates are able to stimulate each others' catalysis by ITPK1. We further show that these features occur in the human protein, but not in plant or protozoan homologues. The high resolution structure of human ITPK1 identifies novel secondary structural features able to impart substrate selectivity and enhance nucleotide binding, thereby promoting intersubstrate phosphate transfer. Our work describes a novel mode of substrate regulation and provides insight into the enzyme evolution of a signaling mechanism from a metabolic role.


  • Organizational Affiliation

    Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Inositol-tetrakisphosphate 1-kinase
A, B
347Homo sapiensMutation(s): 0 
Gene Names: ITPK1
EC: 2.7.1.134 (PDB Primary Data), 2.7.1.159 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for Q13572 (Homo sapiens)
Explore Q13572 
Go to UniProtKB:  Q13572
PHAROS:  Q13572
GTEx:  ENSG00000100605 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ13572
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
ADP
Query on ADP

Download Ideal Coordinates CCD File 
J [auth A],
T [auth B]
ADENOSINE-5'-DIPHOSPHATE
C10 H15 N5 O10 P2
XTWYTFMLZFPYCI-KQYNXXCUSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
C [auth A]
D [auth A]
E [auth A]
F [auth A]
G [auth A]
C [auth A],
D [auth A],
E [auth A],
F [auth A],
G [auth A],
K [auth B],
L [auth B],
M [auth B],
N [auth B],
O [auth B],
P [auth B],
Q [auth B]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
MN
Query on MN

Download Ideal Coordinates CCD File 
H [auth A],
I [auth A],
R [auth B],
S [auth B]
MANGANESE (II) ION
Mn
WAEMQWOKJMHJLA-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.229 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.183 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 62.704α = 90
b = 94.315β = 90
c = 130.242γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
PDB_EXTRACTdata extraction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2007-07-03
    Type: Initial release
  • Version 1.1: 2007-10-23
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Advisory, Version format compliance
  • Version 1.3: 2024-02-21
    Changes: Data collection, Database references, Derived calculations