1HFQ

COMPARISON OF TERNARY CRYSTAL COMPLEXES OF HUMAN DIHYDROFOLATE REDUCTASE WITH NADPH AND A CLASSICAL ANTITUMOR FUROPYRIMDINE


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Work: 0.175 

wwPDB Validation   3D Report Full Report


This is version 1.5 of the entry. See complete history


Literature

Comparison of ternary crystal complexes of F31 variants of human dihydrofolate reductase with NADPH and a classical antitumor furopyrimidine.

Cody, V.Galitsky, N.Luft, J.R.Pangborn, W.Blakley, R.L.Gangjee, A.

(1998) Anticancer Drug Des 13: 307-315

  • Primary Citation of Related Structures:  
    1HFP, 1HFQ, 1HFR

  • PubMed Abstract: 

    The novel furopyrimidine, N-[4-[(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)-methyl]-methylamino] -benzoyl]-L-glutamate (MTXO), a classical antifolate with weak antitumor activity compared with methotrexate (MTX), has been studied as inhibitorcofactor ternary crystal complexes with recombinant Phe-31 to Ser (F31S) and Phe-31 to Gly (F31G) variant human dihydrofolate reductase (hDHFR). Kinetic data show that the binding affinity of MTXO is significantly weaker for the variant hDHFR enzyme than for the wild type enzyme. Structural data for the Phe-31 variants, along with wild type hDHFR, provide the first direct comparison of the binding interactions of a single antifolate in a family of variant hDHFR. These ternary hDHFR complexes crystallize in the rhombohedral space group R3, isomorphous to that reported for wild type hDHFR MTXO-NADPH ternary complex. MTXO binds with its 2,4-diaminofuropyrimidine ring interacting with Glu-30 in hDHFR. The greatest change on modification of the side chain at position 31 is loss of hydrophobic contacts to the inhibitor, which results in the significant decrease in binding affinity of MTXO for the Phe-31 variants. The presence of the 6-5 furopyrimidine ring instead of the 6-6 pteridine ring causes a different bridge conformation compared with MTX, and in the case of the wild type MTXO complex also results in weaker hydrophobic contacts to Phe-31 than observed for MTXT. For the design of antitumor agents related to MTXO, increasing the bridge of MTXO from two to three or four atoms should provide increased DHFR inhibitory potency and antitumor activity.


  • Organizational Affiliation

    Hauptman-Woodward Medical Research Institute, Inc., NY 14203, USA. cody@hwi.buffalo.edu


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
DIHYDROFOLATE REDUCTASE186Homo sapiensMutation(s): 1 
Gene Names: POTENTIAL
EC: 1.5.1.3
UniProt & NIH Common Fund Data Resources
Find proteins for P00374 (Homo sapiens)
Explore P00374 
Go to UniProtKB:  P00374
PHAROS:  P00374
GTEx:  ENSG00000228716 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00374
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NDP
Query on NDP

Download Ideal Coordinates CCD File 
B [auth A]NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE
C21 H30 N7 O17 P3
ACFIXJIJDZMPPO-NNYOXOHSSA-N
MOT
Query on MOT

Download Ideal Coordinates CCD File 
C [auth A]N-[4-[(2,4-DIAMINOFURO[2,3D]PYRIMIDIN-5-YL)METHYL]METHYLAMINO]-BENZOYL]-L-GLUTAMATE
C20 H22 N6 O6
WXINNGCGSCFUCR-ZDUSSCGKSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
MOT Binding MOAD:  1HFQ Ki: 2.7 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Work: 0.175 
  • Space Group: H 3
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 87.12α = 90
b = 87.12β = 90
c = 77.014γ = 120
Software Package:
Software NamePurpose
PROFFTrefinement
R-AXISdata reduction

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 1998-01-28
    Type: Initial release
  • Version 1.1: 2008-03-03
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2013-12-11
    Changes: Non-polymer description
  • Version 1.4: 2021-11-03
    Changes: Database references, Derived calculations, Other
  • Version 1.5: 2024-02-07
    Changes: Data collection