3FL8

Crystal structure of B. anthracis dihydrofolate reductase (DHFR) with RAB1, a TMP-dihydrophthalazine derivative


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.29 Å
  • R-Value Free: 0.254 
  • R-Value Work: 0.206 
  • R-Value Observed: 0.209 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Crystal structure of Bacillus anthracis dihydrofolate reductase with the dihydrophthalazine-based trimethoprim derivative RAB1 provides a structural explanation of potency and selectivity.

Bourne, C.R.Bunce, R.A.Bourne, P.C.Berlin, K.D.Barrow, E.W.Barrow, W.W.

(2009) Antimicrob Agents Chemother 53: 3065-3073

  • DOI: https://doi.org/10.1128/AAC.01666-08
  • Primary Citation of Related Structures:  
    3FL8, 3FL9

  • PubMed Abstract: 

    Bacillus anthracis possesses an innate resistance to the antibiotic trimethoprim due to poor binding to dihydrofolate reductase (DHFR); currently, there are no commercial antibacterials that target this enzyme in B. anthracis. We have previously reported a series of dihydrophthalazine-based trimethoprim derivatives that are inhibitors for this target. In the present work, we have synthesized one compound (RAB1) displaying favorable 50% inhibitory concentration (54 nM) and MIC (< or =12.8 microg/ml) values. RAB1 was cocrystallized with the B. anthracis DHFR in the space group P2(1)2(1)2(1), and X-ray diffraction data were collected to a 2.3-A resolution. Binding of RAB1 causes a conformational change of the side chain of Arg58 and Met37 to accommodate the dihydrophthalazine moiety. Unlike the natural substrate or trimethoprim, the dihydrophthalazine group provides a large hydrophobic anchor that embeds within the DHFR active site and accounts for its selective inhibitory activity against B. anthracis.


  • Organizational Affiliation

    Department of Veterinary Pathobiology, Oklahoma State University, Stillwater, OK 74078, USA. christina.bourne@okstate.edu


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Dihydrofolate reductase
A, B, C, D, E
A, B, C, D, E, F, G, H
166Bacillus anthracisMutation(s): 0 
Gene Names: BAS2083BA_2237dfrADHFRGBAA2237
EC: 1.5.1.3
UniProt
Find proteins for Q81R22 (Bacillus anthracis)
Explore Q81R22 
Go to UniProtKB:  Q81R22
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ81R22
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
RAR
Query on RAR

Download Ideal Coordinates CCD File 
J [auth A]
L [auth B]
N [auth C]
P [auth D]
R [auth E]
J [auth A],
L [auth B],
N [auth C],
P [auth D],
R [auth E],
T [auth F],
V [auth G],
X [auth H]
5-(3,4-dimethoxy-5-{(1E)-3-oxo-3-[(1S)-1-propylphthalazin-2(1H)-yl]prop-1-en-1-yl}benzyl)pyrimidine-2,4-diamine
C27 H30 N6 O3
YGDVMSPWZQHNMB-NEQMZLFVSA-N
CA
Query on CA

Download Ideal Coordinates CCD File 
I [auth A]
K [auth B]
M [auth C]
O [auth D]
Q [auth E]
I [auth A],
K [auth B],
M [auth C],
O [auth D],
Q [auth E],
S [auth F],
U [auth G],
W [auth H]
CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
RAR Binding MOAD:  3FL8 IC50: 54 (nM) from 1 assay(s)
BindingDB:  3FL8 IC50: 54 (nM) from 1 assay(s)
PDBBind:  3FL8 IC50: 54 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.29 Å
  • R-Value Free: 0.254 
  • R-Value Work: 0.206 
  • R-Value Observed: 0.209 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 68.178α = 90
b = 135.92β = 90
c = 168.652γ = 90
Software Package:
Software NamePurpose
PROTEUM PLUSdata collection
PHASERphasing
PHENIXrefinement
SAINTdata reduction
SADABSdata 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: 2009-04-28
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2023-09-06
    Changes: Data collection, Database references, Derived calculations, Refinement description