3MJR

Human dCK complex with Acyclic Nucleoside


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.312 
  • R-Value Work: 0.258 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

The Sugar Ring of the Nucleoside Is Required for Productive Substrate Positioning in the Active Site of Human Deoxycytidine Kinase (dCK): Implications for the Development of dCK-Activated Acyclic Guanine Analogues.

Hazra, S.Konrad, M.Lavie, A.

(2010) J Med Chem 53: 5792-5800

  • DOI: https://doi.org/10.1021/jm1005379
  • Primary Citation of Related Structures:  
    3MJR

  • PubMed Abstract: 

    The low toxicity of acyclovir (ACV) is mainly due to the fact that human nucleoside kinases have undetectable phosphorylation rates with this acyclic guanine analogue. In contrast, herpes virus thymidine kinase (HSV1-TK) readily activates ACV. We wanted to understand why human deoxycytidine kinase (dCK), which is related to HSV1-TK and phosphorylates deoxyguanosine, does not accept acyclic guanine analogues as substrates. Therefore, we crystallized dCK in complex with ACV at the nucleoside phosphoryl acceptor site and UDP at the phosphoryl donor site. The structure reveals that while ACV does bind at the dCK active site, it does so adopting a nonproductive conformation. Despite binding ACV, the enzyme remains in the open, inactive state. In comparison to ACV binding to HSV1-TK, in dCK, the nucleoside base adopts a different orientation related by about a 60 degrees rotation. Our analysis suggests that dCK would phosphorylate acyclic guanine analogues if they can induce a similar rotation.


  • Organizational Affiliation

    Department of Biochemistry and Molecular Genetics University of Illinois at Chicago, Chicago, Illinois 60607, USA.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Deoxycytidine kinase
A, B, C, D
279Homo sapiensMutation(s): 0 
Gene Names: DCK
EC: 2.7.1.74
UniProt & NIH Common Fund Data Resources
Find proteins for P27707 (Homo sapiens)
Explore P27707 
Go to UniProtKB:  P27707
PHAROS:  P27707
GTEx:  ENSG00000156136 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP27707
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.312 
  • R-Value Work: 0.258 
  • Space Group: P 41
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 97.31α = 90
b = 97.31β = 90
c = 121.5γ = 90
Software Package:
Software NamePurpose
CrystalCleardata collection
MOLREPphasing
REFMACrefinement
XDSdata reduction
XDSdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-07-28
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2017-11-08
    Changes: Refinement description
  • Version 1.3: 2023-09-06
    Changes: Data collection, Database references, Derived calculations, Refinement description