Next Article in Journal
Raman Scattering in Non-Stoichiometric Lithium Niobate Crystals with a Low Photorefractive Effect
Next Article in Special Issue
A Novel Substrate-Binding Site in the X-ray Structure of an Oxidized E. coli Glyceraldehyde 3-Phosphate Dehydrogenase Elucidated by Single-Wavelength Anomalous Dispersion
Previous Article in Journal / Special Issue
Trial Direct Phasing Calculation of A Thyroid Hormone Receptor Alpha Structure (4LNW)
Brief Report

The Crystal Structure of the Plasmodium falciparum PdxK Provides an Experimental Model for Pro-Drug Activation

1
Drug Design XB20, Groningen Research Institute of Pharmacy, University of Groningen, 9700 AD Groningen, The Netherlands
2
Department of Medical Oncology & Pneumology, Internal Medicine VIII, University Hospital Tübingen, 72076 Tübingen, Germany
3
Unit for Drug Discovery, Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, 05508-000 São Paulo, Brazil
*
Author to whom correspondence should be addressed.
Crystals 2019, 9(10), 534; https://doi.org/10.3390/cryst9100534
Received: 2 August 2019 / Revised: 10 October 2019 / Accepted: 11 October 2019 / Published: 17 October 2019
(This article belongs to the Special Issue Protein Crystallography)
Pyridoxine/pyridoxal kinase (PdxK), belongs to the ribokinase family and is involved in the vitamin B6 salvage pathway by phosphorylating 5-pyridoxal (PL) into an active form. In the human malaria parasite, Plasmodium falciparum, PfPdxK functions to salvage vitamin B6 from both itself and its host. Here, we report the crystal structure of PfPdxK from P. falciparum in complex with a non-hydrolyzable ATP analog (AMP-PNP) and PL. As expected, the fold is retained and both AMP-PNP and PL occupy the same binding sites when compared to the human ortholog. However, our model allows us to identify a FIxxIIxL motif at the C terminus of the disordered repeat motif (XNXH)m that is implicated in binding the WD40 domain and may provide temporal control of PfPdxK through an interaction with a E3 ligase complex. Furthermore, molecular docking approaches based on our model allow us to explain differential PfPdxK phosphorylation and activation of a novel class of potent antimalarials (PT3, PT5 and PHME), providing a basis for further development of these compounds. Finally, the structure of PfPdxK provides a high-quality model for a better understanding of vitamin B6 synthesis and salvage in the parasite. View Full-Text
Keywords: PfPdxK; motif; PT3; PT5; PHME PfPdxK; motif; PT3; PT5; PHME
Show Figures

Figure 1

MDPI and ACS Style

Gao, K.; Wang, W.; Kronenberger, T.; Wrenger, C.; Groves, M.R. The Crystal Structure of the Plasmodium falciparum PdxK Provides an Experimental Model for Pro-Drug Activation. Crystals 2019, 9, 534. https://doi.org/10.3390/cryst9100534

AMA Style

Gao K, Wang W, Kronenberger T, Wrenger C, Groves MR. The Crystal Structure of the Plasmodium falciparum PdxK Provides an Experimental Model for Pro-Drug Activation. Crystals. 2019; 9(10):534. https://doi.org/10.3390/cryst9100534

Chicago/Turabian Style

Gao, Kai, Wenjia Wang, Thales Kronenberger, Carsten Wrenger, and Matthew R. Groves. 2019. "The Crystal Structure of the Plasmodium falciparum PdxK Provides an Experimental Model for Pro-Drug Activation" Crystals 9, no. 10: 534. https://doi.org/10.3390/cryst9100534

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop