5BRF: Crystal Structure Of Trypanosoma Cruzi Glucokinase In Complex With Inhibitor Hpop-glcn

Glucokinase and hexokinase from pathogenic protozoa Trypanosoma cruzi are potential drug targets for antiparasitic chemotherapy of Chagas' disease. These glucose kinases phosphorylate d-glucose with co-substrate ATP and yield glucose 6-phosphate and are involved in essential metabolic pathways, such as glycolysis and the pentose phosphate pathway. An inhibitor class was conceived that is selective for T. cruzi glucokinase (TcGlcK) using structure-based drug design involving glucosamine having a linker from the C2 amino that terminates with a hydrophobic group either being phenyl, p-hydroxyphenyl, or dioxobenzo[b]thiophenyl groups. The synthesis and characterization for two of the four compounds are presented while the other two compounds were commercially available. Four high-resolution X-ray crystal structures of TcGlcK inhibitor complexes are reported along with enzyme inhibition constants (Ki) for TcGlcK and Homo sapiens hexokinase IV (HsHxKIV). These glucosamine analogue inhibitors include three strongly selective TcGlcK inhibitors and a fourth inhibitor, benzoyl glucosamine (BENZ-GlcN), which is a similar variant exhibiting a shorter linker. Carboxybenzyl glucosamine (CBZ-GlcN) was found to be the strongest glucokinase inhibitor known to date, having a Ki of 0.71+/-0.05muM. Also reported are two biologically active inhibitors against in vitro T. cruzi culture that were BENZ-GlcN and CBZ-GlcN, with intracellular amastigote growth inhibition IC50 values of 16.08+/-0.16muM and 48.73+/-0.69muM, respectively. These compounds revealed little to no toxicity against mammalian NIH-3T3 fibroblasts and provide a key starting point for further drug development with this class of compound.
PDB ID: 5BRFDownload
MMDB ID: 130223
PDB Deposition Date: 2015/5/30
Updated in MMDB: 2015/12
Experimental Method:
x-ray diffraction
Resolution: 2.1  Å
Source Organism:
Similar Structures:
Biological Unit for 5BRF: dimeric; determined by author and by software (PISA)
Molecular Components in 5BRF
Label Count Molecule
Proteins (2 molecules)
Glucokinase 1, Putative
Molecule annotation
Chemicals (2 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB