1SEJ

Crystal Structure of Dihydrofolate Reductase-Thymidylate Synthase from Cryptosporidium hominis Bound to 1843U89/NADPH/dUMP

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.87 Å
  • R-Value Free: 0.237 
  • R-Value Work: 0.220 
  • R-Value Observed: 0.220 

Starting Model: experimental
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This is version 1.4 of the entry. See complete history. 


Literature

Two crystal structures of dihydrofolate reductase-thymidylate synthase from Cryptosporidium hominis reveal protein-ligand interactions including a structural basis for observed antifolate resistance.

Anderson, A.C.

(2005) Acta Crystallogr Sect F Struct Biol Cryst Commun 61: 258-262

  • DOI: https://doi.org/10.1107/S1744309105002435
  • Primary Citation of Related Structures:  
    1SEJ

  • PubMed Abstract: 

    Cryptosporidium hominis is a protozoan parasite that causes acute gastrointestinal illness. There are no effective therapies for cryptosporidiosis, highlighting the need for new drug-lead discovery. An analysis of the protein-ligand interactions in two crystal structures of dihydrofolate reductase-thymidylate synthase (DHFR-TS) from C. hominis, determined at 2.8 and 2.87 A resolution, reveals that the interactions of residues Ile29, Thr58 and Cys113 in the active site of C. hominis DHFR provide a possible structural basis for the observed antifolate resistance. A comparison with the structure of human DHFR reveals active-site differences that may be exploited for the design of species-selective inhibitors.

    • Organizational Affiliation: 

    Department of Chemistry, Dartmouth College, Hanover, NH 03755, USA. [email protected]


Macromolecules
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(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
bifunctional dihydrofolate reductase-thymidylate synthase
A, B, C, D, E
521Cryptosporidium hominisMutation(s): 0 
EC: 2.1.1.45 (PDB Primary Data), 1.5.1.3 (PDB Primary Data)
UniProt
Find proteins for Q27552 (Cryptosporidium parvum)
Explore Q27552 
Go to UniProtKB:  Q27552
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ27552
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NDP
Query on NDP
Download Ideal Coordinates CCD File 
I [auth A],
M [auth B],
Q [auth C],
U [auth D],
Y [auth E]		NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE
C21 H30 N7 O17 P3
ACFIXJIJDZMPPO-NNYOXOHSSA-N
F89
Query on F89
Download Ideal Coordinates CCD File 
G [auth A]
H [auth A]
K [auth B]
L [auth B]
O [auth C]
G [auth A],
H [auth A],
K [auth B],
L [auth B],
O [auth C],
P [auth C],
S [auth D],
T [auth D],
W [auth E],
X [auth E]
S)-2-(5(((1,2-DIHYDRO-3-METHYL-1-OXOBENZO(F)QUINAZOLIN-9-YL)METHYL)AMINO)1-OXO-2-ISOINDOLINYL)GLUTARIC ACID
C27 H24 N4 O6
BRVFNEZMTRVUGW-QFIPXVFZSA-N
UMP
Query on UMP
Download Ideal Coordinates CCD File 
F [auth A],
J [auth B],
N [auth C],
R [auth D],
V [auth E]		2'-DEOXYURIDINE 5'-MONOPHOSPHATE
C9 H13 N2 O8 P
JSRLJPSBLDHEIO-SHYZEUOFSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.87 Å
  • R-Value Free: 0.237 
  • R-Value Work: 0.220 
  • R-Value Observed: 0.220 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 214.9α = 90
b = 116.3β = 95.23
c = 219.7γ = 90
Software Package:
Software NamePurpose
CNSrefinement
MAR345data collection
SCALEPACKdata scaling
CNSphasing

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2004-05-18
    Type: Initial release
  • Version 1.1: 2008-04-29
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2017-10-11
    Changes: Refinement description
  • Version 1.4: 2023-08-23
    Changes: Data collection, Database references, Derived calculations, Refinement description