5KM1

Human Histidine Triad Nucleotide Binding Protein 1 (hHint1) GMP catalytic product complex


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.65 Å
  • R-Value Free: 0.180 
  • R-Value Work: 0.148 
  • R-Value Observed: 0.150 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

A Crystal Structure Based Guide to the Design of Human Histidine Triad Nucleotide Binding Protein 1 (hHint1) Activated ProTides.

Maize, K.M.Shah, R.Strom, A.Kumarapperuma, S.Zhou, A.Wagner, C.R.Finzel, B.C.

(2017) Mol Pharm 14: 3987-3997

  • DOI: https://doi.org/10.1021/acs.molpharmaceut.7b00664
  • Primary Citation of Related Structures:  
    5KLY, 5KLZ, 5KM0, 5KM1, 5KM2, 5KM3, 5KM4, 5KM5, 5KM6, 5KM8, 5KM9, 5KMA, 5KMB, 5WA8, 5WA9, 6B42

  • PubMed Abstract: 

    Nucleotide analogues that incorporate a metabolically labile nucleoside phosphoramidate (a ProTide) have found utility as prodrugs. In humans, ProTides can be cleaved by human histidine triad nucleotide binding protein 1 (hHint1) to expose the nucleotide monophosphate. Activation by this route circumvents highly selective nucleoside kinases that limit the use of nucleosides as prodrugs. To better understand the diversity of potential substrates of hHint1, we created and studied a series of phosphoramidate nucleosides. Using a combination of enzyme kinetics, X-ray crystallography, and isothermal titration calorimetry with both wild-type and inactive mutant enzymes, we have been able to explore the energetics of substrate binding and establish a structural basis for catalytic efficiency. Diverse nucleobases are well tolerated, but portions of the ribose are needed to position substrates for catalysis. Beneficial characteristics of the amine leaving group are also revealed. Structural principles revealed by these results may be exploited to tune the rate of substrate hydrolysis to strategically alter the intracellular release of the product nucleoside monophosphate from the ProTide.


  • Organizational Affiliation

    Department of Medicinal Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Histidine triad nucleotide-binding protein 1
A, B
129Homo sapiensMutation(s): 0 
Gene Names: HINT1HINT
EC: 3
UniProt & NIH Common Fund Data Resources
Find proteins for P49773 (Homo sapiens)
Explore P49773 
Go to UniProtKB:  P49773
PHAROS:  P49773
GTEx:  ENSG00000169567 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP49773
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
5GP
Query on 5GP

Download Ideal Coordinates CCD File 
C [auth A]GUANOSINE-5'-MONOPHOSPHATE
C10 H14 N5 O8 P
RQFCJASXJCIDSX-UUOKFMHZSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
D [auth A]1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.65 Å
  • R-Value Free: 0.180 
  • R-Value Work: 0.148 
  • R-Value Observed: 0.150 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 78.624α = 90
b = 46.332β = 94.48
c = 64.11γ = 90
Software Package:
Software NamePurpose
Aimlessdata scaling
PHASERphasing
PHENIXrefinement
PDB_EXTRACTdata extraction
XDSdata reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-06-28
    Type: Initial release
  • Version 1.1: 2017-07-26
    Changes: Database references
  • Version 1.2: 2017-10-18
    Changes: Database references
  • Version 1.3: 2017-11-15
    Changes: Database references
  • Version 1.4: 2023-09-27
    Changes: Data collection, Database references, Refinement description