4OR7: Klebsiella Pneumoniae Dihydrofolate Reductase Complexed With Nadph And 6-ethyl-5-{3-[3-(pyrimidin-5-yl)phenyl]prop-1-yn-1-yl}pyrimidine-2,4- Diamine

Resistance to the antibacterial antifolate trimethoprim (TMP) is increasing in members of the family Enterobacteriaceae, driving the design of next-generation antifolates effective against these Gram-negative pathogens. The propargyl-linked antifolates are potent inhibitors of dihydrofolate reductases (DHFR) from several TMP-sensitive and -resistant species, including Klebsiella pneumoniae. Recently, we have determined that these antifolates inhibit the growth of strains of K. pneumoniae, some with MIC values of 1 mug/ml. In order to further the design of potent and selective antifolates against members of the Enterobacteriaceae, we determined the first crystal structures of K. pneumoniae DHFR bound to two of the propargyl-linked antifolates. These structures highlight that interactions with Leu 28, Ile 50, Ile 94, and Leu 54 are necessary for potency; comparison with structures of human DHFR bound to the same inhibitors reveal differences in residues (N64E, P61G, F31L, and V115I) and loop conformations (residues 49 to 53) that may be exploited for selectivity.
PDB ID: 4OR7Download
MMDB ID: 125202
PDB Deposition Date: 2014/2/11
Updated in MMDB: 2014/12
Experimental Method:
x-ray diffraction
Resolution: 1.76  Å
Source Organism:
Similar Structures:
Biological Unit for 4OR7: monomeric; determined by author and by software (PISA)
Molecular Components in 4OR7
Label Count Molecule
Protein (1 molecule)
Dihydrofolate Reductase
Molecule annotation
Chemicals (2 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB