7N7O

Crystal Structure of PI5P4KIIAlpha complex with Palbociclib


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.253 
  • R-Value Work: 0.197 
  • R-Value Observed: 0.200 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Pharmacological inhibition of PI5P4K alpha / beta disrupts cell energy metabolism and selectively kills p53-null tumor cells.

Chen, S.Chandra Tjin, C.Gao, X.Xue, Y.Jiao, H.Zhang, R.Wu, M.He, Z.Ellman, J.Ha, Y.

(2021) Proc Natl Acad Sci U S A 118

  • DOI: https://doi.org/10.1073/pnas.2002486118
  • Primary Citation of Related Structures:  
    7N6Z, 7N71, 7N7J, 7N7K, 7N7L, 7N7M, 7N7N, 7N7O, 7N80, 7N81

  • PubMed Abstract: 

    Most human cancer cells harbor loss-of-function mutations in the p53 tumor suppressor gene. Genetic experiments have shown that phosphatidylinositol 5-phosphate 4-kinase α and β (PI5P4Kα and PI5P4Kβ) are essential for the development of late-onset tumors in mice with germline p53 deletion, but the mechanism underlying this acquired dependence remains unclear. PI5P4K has been previously implicated in metabolic regulation. Here, we show that inhibition of PI5P4Kα/β kinase activity by a potent and selective small-molecule probe disrupts cell energy homeostasis, causing AMPK activation and mTORC1 inhibition in a variety of cell types. Feedback through the S6K/insulin receptor substrate (IRS) loop contributes to insulin hypersensitivity and enhanced PI3K signaling in terminally differentiated myotubes. Most significantly, the energy stress induced by PI5P4Kαβ inhibition is selectively toxic toward p53-null tumor cells. The chemical probe, and the structural basis for its exquisite specificity, provide a promising platform for further development, which may lead to a novel class of diabetes and cancer drugs.


  • Organizational Affiliation

    Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha377Homo sapiensMutation(s): 0 
Gene Names: PIP4K2API5P4KAPIP5K2PIP5K2A
EC: 2.7.1.149
UniProt & NIH Common Fund Data Resources
Find proteins for P48426 (Homo sapiens)
Explore P48426 
Go to UniProtKB:  P48426
PHAROS:  P48426
GTEx:  ENSG00000150867 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP48426
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
LQQ (Subject of Investigation/LOI)
Query on LQQ

Download Ideal Coordinates CCD File 
B [auth A]6-ACETYL-8-CYCLOPENTYL-5-METHYL-2-[(5-PIPERAZIN-1-YLPYRIDIN-2-YL)AMINO]PYRIDO[2,3-D]PYRIMIDIN-7(8H)-ONE
C24 H29 N7 O2
AHJRHEGDXFFMBM-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Binding Affinity Annotations 
IDSourceBinding Affinity
LQQ BindingDB:  7N7O IC50: 208 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.253 
  • R-Value Work: 0.197 
  • R-Value Observed: 0.200 
  • Space Group: P 61 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 135.901α = 90
b = 135.901β = 90
c = 95.014γ = 120
Software Package:
Software NamePurpose
HKL-2000data scaling
REFMACrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
REFMACphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2021-06-30
    Type: Initial release
  • Version 1.1: 2021-07-28
    Changes: Database references
  • Version 1.2: 2023-10-04
    Changes: Data collection, Database references
  • Version 1.3: 2023-10-18
    Changes: Refinement description