4AQL

HUMAN GUANINE DEAMINASE IN COMPLEX WITH VALACYCLOVIR


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.99 Å
  • R-Value Free: 0.214 
  • R-Value Work: 0.180 
  • R-Value Observed: 0.182 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Pan-Pathway Based Interaction Profiling of Fda-Approved Nucleoside and Nucleobase Analogs with Enzymes of the Human Nucleotide Metabolism.

Egeblad, L.Welin, M.Flodin, S.Graslund, S.Wang, L.Balzarini, J.Eriksson, S.Nordlund, P.

(2012) PLoS One 7: 37724

  • DOI: https://doi.org/10.1371/journal.pone.0037724
  • Primary Citation of Related Structures:  
    4AQL

  • PubMed Abstract: 

    To identify interactions a nucleoside analog library (NAL) consisting of 45 FDA-approved nucleoside analogs was screened against 23 enzymes of the human nucleotide metabolism using a thermal shift assay. The method was validated with deoxycytidine kinase; eight interactions known from the literature were detected and five additional interactions were revealed after the addition of ATP, the second substrate. The NAL screening gave relatively few significant hits, supporting a low rate of "off target effects." However, unexpected ligands were identified for two catabolic enzymes guanine deaminase (GDA) and uridine phosphorylase 1 (UPP1). An acyclic guanosine prodrug analog, valaciclovir, was shown to stabilize GDA to the same degree as the natural substrate, guanine, with a ΔT(agg) around 7°C. Aciclovir, penciclovir, ganciclovir, thioguanine and mercaptopurine were also identified as ligands for GDA. The crystal structure of GDA with valaciclovir bound in the active site was determined, revealing the binding of the long unbranched chain of valaciclovir in the active site of the enzyme. Several ligands were identified for UPP1: vidarabine, an antiviral nucleoside analog, as well as trifluridine, idoxuridine, floxuridine, zidovudine, telbivudine, fluorouracil and thioguanine caused concentration-dependent stabilization of UPP1. A kinetic study of UPP1 with vidarabine revealed that vidarabine was a mixed-type competitive inhibitor with the natural substrate uridine. The unexpected ligands identified for UPP1 and GDA imply further metabolic consequences for these nucleoside analogs, which could also serve as a starting point for future drug design.


  • Organizational Affiliation

    Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
GUANINE DEAMINASE476Homo sapiensMutation(s): 0 
EC: 3.5.4.3
UniProt & NIH Common Fund Data Resources
Find proteins for Q9Y2T3 (Homo sapiens)
Explore Q9Y2T3 
Go to UniProtKB:  Q9Y2T3
PHAROS:  Q9Y2T3
GTEx:  ENSG00000119125 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9Y2T3
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
TXC
Query on TXC

Download Ideal Coordinates CCD File 
C [auth A]2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]ethyl L-valinate
C13 H20 N6 O4
HDOVUKNUBWVHOX-QMMMGPOBSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
B [auth A]ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.99 Å
  • R-Value Free: 0.214 
  • R-Value Work: 0.180 
  • R-Value Observed: 0.182 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 86.729α = 90
b = 91.383β = 90
c = 131.913γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
SCALAdata scaling
MOLREPphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2012-05-02
    Type: Initial release
  • Version 1.1: 2012-07-25
    Changes: Database references
  • Version 1.2: 2023-12-20
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description