PDBsum entry 3eem

Oxidoreductase

PDB id: 3eem

Contents

Protein chains

225 a.a. *

Ligands

NDP ×2

53V ×2

Waters ×205

* Residue conservation analysis

PDB id:

3eem

Name:

Oxidoreductase

Title:

Candida glabrata dihydrofolate reductase complexed with 2,4-diamino-5- [3-methyl-3-(3-methoxy-5-(2,6-dimethylphenyl)phenyl)prop-1-ynyl]-6- methylpyrimidine(ucp111d26m) and NADPH

Structure:

Dihydrofolate reductase. Chain: a, b. Engineered: yes

Source:

Candida glabrata. Yeast. Organism_taxid: 5478. Gene: cagl0j03894g. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.11Å R-factor: 0.172 R-free: 0.230

Authors:

J.Liu,A.Anderson

Key ref:

J.Liu et al. (2009). Probing the active site of Candida glabrata dihydrofolate reductase with high resolution crystal structures and the synthesis of new inhibitors. Chem Biol Drug Des, 73, 62-74. PubMed id: 19152636

Date:

04-Sep-08 Release date: 18-Aug-09

Protein chains

Q6FPH0  (Q6FPH0_CANGA) -  Dihydrofolate reductase from Candida glabrata (strain ATCC 2001 / BCRC 20586 / JCM 3761 / NBRC 0622 / NRRL Y-65 / CBS 138)

Seq: 217 a.a.

Struc: 225 a.a.

Enzyme reactions

• Enzyme class: E.C.1.5.1.3 - dihydrofolate reductase.
• Pathway: Folate Coenzymes
• Reaction: (6S)-5,6,7,8-tetrahydrofolate + NADP⁺ = 7,8-dihydrofolate + NADPH + H⁺

(6S)-5,6,7,8-tetrahydrofolate + NADP(+) (Bound ligand (Het Group name = NDP) corresponds exactly) = 7,8-dihydrofolate + NADPH + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

Chem Biol Drug Des 73:62-74 (2009)

PubMed id: 19152636

Probing the active site of Candida glabrata dihydrofolate reductase with high resolution crystal structures and the synthesis of new inhibitors.

J.Liu, D.B.Bolstad, A.E.Smith, N.D.Priestley, D.L.Wright, A.C.Anderson.

ABSTRACT

Candida glabrata, a fungal strain resistant to many commonly administered antifungal agents, has become an emerging threat to human health. In previous work, we validated that the essential enzyme, dihydrofolate reductase, is a drug target in C. glabrata. Using a crystal structure of dihydrofolate reductase from C. glabrata bound to an initial lead compound, we designed a class of biphenyl antifolates that potently and selectively inhibit both the enzyme and the growth of the fungal culture. In this work, we explore the structure-activity relationships of this class of antifolates with four new high resolution crystal structures of enzyme:inhibitor complexes and the synthesis of four new inhibitors. The designed inhibitors are intended to probe key hydrophobic pockets visible in the crystal structure. The crystal structures and an evaluation of the new compounds reveal that methyl groups at the meta and para positions of the distal phenyl ring achieve the greatest number of interactions with the pathogenic enzyme and the greatest degree of selectivity over the human enzyme. Additionally, antifungal activity can be tuned with substitution patterns at the propargyl and para-phenyl positions.