7S49

Crystal Structure of Inhibitor-bound Galactokinase

  • Classification: Transferase/Inhibitor
  • Organism(s): Homo sapiens
  • Expression System: Escherichia coli
  • Mutation(s): Yes 

  • Deposited: 2021-09-08 Released: 2021-09-29 
  • Deposition Author(s): Whitby, F.G.
  • Funding Organization(s): National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.226 
  • R-Value Work: 0.158 
  • R-Value Observed: 0.160 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Structure-Based Optimization of Small Molecule Human Galactokinase Inhibitors.

Liu, L.Tang, M.Pragani, R.Whitby, F.G.Zhang, Y.Q.Balakrishnan, B.Fang, Y.Karavadhi, S.Tao, D.LeClair, C.A.Hall, M.D.Marugan, J.J.Boxer, M.Shen, M.Hill, C.P.Lai, K.Patnaik, S.

(2021) J Med Chem 64: 13551-13571

  • DOI: https://doi.org/10.1021/acs.jmedchem.1c00945
  • Primary Citation of Related Structures:  
    7RCL, 7RCM, 7S49, 7S4C

  • PubMed Abstract: 

    Classic galactosemia is a rare disease caused by inherited deficiency of galactose-1 phosphate uridylyltransferase (GALT). Accumulation of galactose-1 phosphate (gal-1P) is thought to be the major cause of the chronic complications associated with this disease, which currently has no treatment. Inhibiting galactokinase (GALK1), the enzyme that generates galactose-1 phosphate, has been proposed as a novel strategy for treating classic galactosemia. Our previous work identified a highly selective unique dihydropyrimidine inhibitor against GALK1. With the determination of a co-crystal structure of this inhibitor with human GALK1, we initiated a structure-based structure-activity relationship (SAR) optimization campaign that yielded novel analogs with potent biochemical inhibition (IC 50 < 100 nM). Lead compounds were also able to prevent gal-1P accumulation in patient-derived cells at low micromolar concentrations and have pharmacokinetic properties suitable for evaluation in rodent models of galactosemia.


  • Organizational Affiliation

    National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Galactokinase
A, B
392Homo sapiensMutation(s): 2 
Gene Names: GALK1GALK
EC: 2.7.1.6
UniProt & NIH Common Fund Data Resources
Find proteins for P51570 (Homo sapiens)
Explore P51570 
Go to UniProtKB:  P51570
PHAROS:  P51570
GTEx:  ENSG00000108479 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP51570
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
4QI (Subject of Investigation/LOI)
Query on 4QI

Download Ideal Coordinates CCD File 
D [auth A],
J [auth B]
(4R)-2-[(1,3-benzoxazol-2-yl)amino]-4-(4-chloro-1H-pyrazol-5-yl)-4,6,7,8-tetrahydroquinazolin-5(1H)-one
C18 H15 Cl N6 O2
ORBGGGFENULXFO-MRXNPFEDSA-N
GLA
Query on GLA

Download Ideal Coordinates CCD File 
C [auth A],
I [auth B]
alpha-D-galactopyranose
C6 H12 O6
WQZGKKKJIJFFOK-PHYPRBDBSA-N
PO4
Query on PO4

Download Ideal Coordinates CCD File 
E [auth A],
F [auth A],
G [auth A],
K [auth B]
PHOSPHATE ION
O4 P
NBIIXXVUZAFLBC-UHFFFAOYSA-K
NA
Query on NA

Download Ideal Coordinates CCD File 
H [auth A],
L [auth B]
SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.226 
  • R-Value Work: 0.158 
  • R-Value Observed: 0.160 
  • Space Group: P 61 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 129.407α = 90
b = 129.407β = 90
c = 240.548γ = 120
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
PHENIXphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data

  • Released Date: 2021-09-29 
  • Deposition Author(s): Whitby, F.G.

Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesRO1HD074844

Revision History  (Full details and data files)

  • Version 1.0: 2021-09-29
    Type: Initial release
  • Version 1.1: 2021-10-06
    Changes: Database references
  • Version 1.2: 2023-02-01
    Changes: Advisory, Database references
  • Version 1.3: 2023-10-25
    Changes: Data collection, Refinement description
  • Version 1.4: 2024-10-30
    Changes: Structure summary