1E2M

HPT + HMTT


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.262 
  • R-Value Work: 0.217 

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This is version 1.3 of the entry. See complete history


Literature

The Effect of Substrate Binding on the Conformation and Structural Stability of Herpes Simplex Virus Type 1 Thymidine Kinase

Wurth, C.Kessler, U.Vogt, J.Schulz, G.E.Folkers, G.Scapozza, L.

(2001) Protein Sci 10: 63

  • DOI: https://doi.org/10.1110/ps.27401
  • Primary Citation of Related Structures:  
    1E2M, 1E2N, 1E2P

  • PubMed Abstract: 

    The structure of Herpes simplex virus type 1 thymidine kinase (TK(HSV1)) is known at high resolution in complex with a series of ligands and exhibits important structural similarities to the nucleoside monophosphate (NMP) kinase family, which are known to show large conformational changes upon binding of substrates. The effect of substrate binding on the conformation and structural stability of TK(HSV1), measured by thermal denaturation experiments, far-UV circular dichroism (CD) and fluorescence is described, and the results indicate that the conformation of the ligand-free TK(HSV1) is less ordered and less stable compared to the ligated enzyme. Furthermore, two crystal structures of TK(HSV1) in complex with two new ligands, HPT and HMTT, refined to 2.2 A are presented. Although TK(HSV1):HPT does not exhibit any significant deviations from the model of TK(HSV1):dT, the TK(HSV1):HMTT complex displays a unique conformationally altered active site resulting in a lowered thermal stability of this complex. Moreover, we show that binding affinity and binding mode of the ligand correlate with thermal stability of the complex. We use this correlation to propose a method to estimate binding constants for new TK(HSV1)substrates using thermal denaturation measurements monitored by CD spectroscopy. The kinetic and structural results of both test substrates HPT and HMTT show that the CD thermal denaturation system is very sensitive to conformational changes caused by unusual binding of a substrate analog.


  • Organizational Affiliation

    Department of Applied BioSciences, Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, CH-8057 Zürich, Switzerland.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
THYMIDINE KINASE
A, B
331Human alphaherpesvirus 1 strain 17Mutation(s): 0 
EC: 2.7.1.21
UniProt
Find proteins for P0DTH5 (Human herpesvirus 1 (strain 17))
Explore P0DTH5 
Go to UniProtKB:  P0DTH5
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP0DTH5
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.262 
  • R-Value Work: 0.217 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 113.7α = 90
b = 117.2β = 90
c = 108.5γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling
AMoREphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2001-03-31
    Type: Initial release
  • Version 1.1: 2011-05-08
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2023-12-06
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description