PDBsum entry 3kjs

Oxidoreductase,transferase

PDB id: 3kjs

Contents

Protein chains

500 a.a. *

Ligands

DQ1 ×4

NAP ×4

SO4 ×8

EDO ×13

Waters ×737

* Residue conservation analysis

PDB id:

3kjs

Name:

Oxidoreductase,transferase

Title:

Crystal structure of t. Cruzi dhfr-ts with 3 high affinity dhfr inhibitors: dq1 inhibitor complex

Structure:

Dihydrofolate reductase-thymidylate synthase. Chain: a, b, c, d. Engineered: yes

Source:

Trypanosoma cruzi. Organism_taxid: 5693. Strain: y. Gene: dhfrts. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.50Å R-factor: 0.202 R-free: 0.234

Authors:

N.Schormann,O.Senkovich,D.Chattopadhyay

Key ref:

N.Schormann et al. (2010). Synthesis and characterization of potent inhibitors of Trypanosoma cruzi dihydrofolate reductase. Bioorg Med Chem Lett, 18, 4056-4066. PubMed id: 20452776

Date:

03-Nov-09 Release date: 09-Jun-10

Protein chains

Q8T5T8  (Q8T5T8_TRYCR) -  Bifunctional dihydrofolate reductase-thymidylate synthase from Trypanosoma cruzi

Seq: 521 a.a.

Struc: 500 a.a.

Enzyme reactions

• Enzyme class 2: 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 = NAP) corresponds exactly) = 7,8-dihydrofolate + NADPH + H(+)

• Enzyme class 3: E.C.2.1.1.45 - thymidylate synthase.

Pathway:

• Reaction: dUMP + (6R)-5,10-methylene-5,6,7,8-tetrahydrofolate = 7,8-dihydrofolate + dTMP

dUMP + (6R)-5,10-methylene-5,6,7,8-tetrahydrofolate = 7,8-dihydrofolate + dTMP (Bound ligand (Het Group name = NAP) matches with 40.82% similarity)

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

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

reference

Bioorg Med Chem Lett 18:4056-4066 (2010)

PubMed id: 20452776

Synthesis and characterization of potent inhibitors of Trypanosoma cruzi dihydrofolate reductase.

N.Schormann, S.E.Velu, S.Murugesan, O.Senkovich, K.Walker, B.C.Chenna, B.Shinkre, A.Desai, D.Chattopadhyay.

ABSTRACT

Dihydrofolate reductase (DHFR) of the parasite Trypanosoma cruzi (T. cruzi) is a potential target for developing drugs to treat Chagas' disease. We have undertaken a detailed structure-activity study of this enzyme. We report here synthesis and characterization of six potent inhibitors of the parasitic enzyme. Inhibitory activity of each compound was determined against T. cruzi and human DHFR. One of these compounds, ethyl 4-(5-[(2,4-diamino-6-quinazolinyl)methyl]amino-2-methoxyphenoxy)butanoate (6b) was co-crystallized with the bifunctional dihydrofolate reductase-thymidylate synthase enzyme of T. cruzi and the crystal structure of the ternary enzyme:cofactor:inhibitor complex was determined. Molecular docking was used to analyze the potential interactions of all inhibitors with T. cruzi DHFR and human DHFR. Inhibitory activities of these compounds are discussed in the light of enzyme-ligand interactions. Binding affinities of each inhibitor for the respective enzymes were calculated based on the experimental or docked binding mode. An estimated 60-70% of the total binding energy is contributed by the 2,4-diaminoquinazoline scaffold.