6PF4

Crystal structure of human thymidylate synthase Delta (7-29) in complex with dUMP and 2-(2-(4-((2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)methyl)benzamido)phenyl)acetic acid


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.85 Å
  • R-Value Free: 0.254 
  • R-Value Work: 0.239 
  • R-Value Observed: 0.239 

wwPDB Validation   3D Report Full Report

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This is version 1.2 of the entry. See complete history


Literature

Structure activity relationship towards design of cryptosporidium specific thymidylate synthase inhibitors.

Czyzyk, D.J.Valhondo, M.Deiana, L.Tirado-Rives, J.Jorgensen, W.L.Anderson, K.S.

(2019) Eur J Med Chem 183: 111673-111673

  • DOI: https://doi.org/10.1016/j.ejmech.2019.111673
  • Primary Citation of Related Structures:  
    6PF3, 6PF4, 6PF5, 6PF6, 6PF7, 6PF8, 6PF9, 6PFA, 6PFB, 6PFC, 6PFD, 6PFE, 6PFF, 6PFG, 6PFH, 6PFI

  • PubMed Abstract: 

    Cryptosporidiosis is a human gastrointestinal disease caused by protozoans of the genus Cryptosporidium, which can be fatal in immunocompromised individuals. The essential enzyme, thymidylate synthase (TS), is responsible for de novo synthesis of deoxythymidine monophosphate. The TS active site is relatively conserved between Cryptosporidium and human enzymes. In previous work, we identified compound 1, (2-amino-4-oxo-4,7-dihydro-pyrrolo[2,3-d]pyrimidin-methyl-phenyl-l-glutamic acid), as a promising selective Cryptosporidium hominis TS (ChTS) inhibitor. In the present study, we explore the structure-activity relationship around 1 glutamate moiety by synthesizing and biochemically evaluating the inhibitory activity of analogues against ChTS and human TS (hTS). X-Ray crystal structures were obtained for compounds bound to both ChTS and hTS. We establish the importance of the 2-phenylacetic acid moiety methylene linker in optimally positioning compounds 23, 24, and 25 within the active site. Moreover, through the comparison of structural data for 5, 14, 15, and 23 bound in both ChTS and hTS identified that active site rigidity is a driving force in determining inhibitor selectivity.


  • Organizational Affiliation

    Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06520, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Thymidylate synthaseA [auth B],
B [auth A],
C,
D
290Homo sapiensMutation(s): 0 
Gene Names: TYMSTSOK/SW-cl.29
EC: 2.1.1.45
UniProt & NIH Common Fund Data Resources
Find proteins for P04818 (Homo sapiens)
Explore P04818 
Go to UniProtKB:  P04818
PHAROS:  P04818
GTEx:  ENSG00000176890 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP04818
Sequence Annotations
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  • Reference Sequence
Small Molecules
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.85 Å
  • R-Value Free: 0.254 
  • R-Value Work: 0.239 
  • R-Value Observed: 0.239 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 92.19α = 90
b = 96.437β = 90
c = 135.719γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
XDSdata scaling
PHASERphasing

Structure Validation

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Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)United StatesAI083146
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)United States5T32AI007404

Revision History  (Full details and data files)

  • Version 1.0: 2019-10-02
    Type: Initial release
  • Version 1.1: 2019-12-18
    Changes: Author supporting evidence
  • Version 1.2: 2023-10-11
    Changes: Data collection, Database references, Refinement description