issue contents

Journal logoSTRUCTURAL BIOLOGY
COMMUNICATIONS
ISSN: 2053-230X

May 2015 issue

Molecular parasitology - advances in biology and supporting drug discovery

Highlighted illustration

Cover illustration: Crystal structure of Plasmodium falciparum dihydroorotate dehydrogenase in complex with DSM267 and FMN. Exploiting the hydrophobic `tunnel' to the FMN binding site enabled the structure-guided design of a potent and selective inhibitor of P. falciparum DHODH. For more details see the overview of the role of three-dimensional structures in the design of therapeutics targeting parasitic protozoa in this issue (Hol, p. 485).

molecular parasitology



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A review and historical perspective covering the many different aspects of antiparasitic drug discovery, in particular targeting protists, is presented. The key role of structural studies in the process is highlighted and specific high-profile examples are given.

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In this review, current structural understanding of the apicomplexan glideosome and actin regulation is described.

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Parasitic protozoans of the Plasmodium genus are responsible for malaria, a disease that kills approximately one child every minute in Africa and ∼2000 people per day worldwide. Here, the solution structure of the 84-residue BolA protein PFE0790c from the deadliest Plasmodium species, P. falciparum, is reported.

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Cryptosporidium parvum is the primary protozoan parasite from the Cryptosporidium genus responsible for cryptosporidiosis in humans. Here, the 2.0 Å resolution structure of the divalent-cation tolerance protein CutA1 encoded in the genome of C. parvum Iowa II is described.

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Compound P131 displays antiparasitic activity in a mouse model of Cryptosporidium infection, validating IMP dehydrogenase (IMPDH) as a drug target. Here, the structure of the enzyme–substrate–P131 complex is reported at 2.05 Å resolution. The structure is an important step to further refine the design of IMPDH inhibitors.

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The structure of a tubulin-binding cofactor from L. major is reported and compared with yeast, plant and human orthologues.

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The crystal structure of L. (V.) braziliensis dihydroorotate dehydrogenase, a potential target for drug development against cutaneous leishmaniasis, is reported.

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The X-ray structure of the antimalarial drug target dihydroorotate dehydrogenase bound to a potent and selective benzamide-based inhibitor shows novel binding-site interactions.

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Uridine diphosphate N-acetylglucosamine pyrophosphorylase (UAP) synthesizes UDP-GlcNAc. E. histolytica UAP appears to lack the N-terminal extension of UAP from other parasites that is partially involved in allosteric regulation by small-molecule inhibitors.

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Structures of aspartate aminotransferases from eukaryotic pathogens were solved in complex with pyridoxal phosphate. The four structures show either the open or the closed conformation of the enzyme.

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Structures of the histidine triad family protein from E. histolytica were solved in complex with sulfate, AMP or GMP. The three structures show very similar nucleotide poses, with the sulfate occupying the same space as the α-phosphate of the nucleotides.

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The production, purification and crystallization of a recently identified trans-sialidase from T. vivax is described. The purified enzyme is active and produces diffraction-quality crystals using the sitting-drop vapour-diffusion method. The crystals belonged to space group P212121 and diffracted to 2.5 Å resolution.

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N-Myristoyltransferase (NMT) has been shown to be an attractive target for the development of novel therapeutic agents for the treatment of human African trypanosomiasis. A fragment library has been screened using NMR spectroscopy and the binding mode of the hits was confirmed by X-ray crystallography using L. major NMT as a structural surrogate.

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ADP-ribosylation factors (ARFs) are highly conserved proteins present in all eukarya. The structure of ARF1 from E. histolytica is described and compared with orthologs from other species.

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P. falciparum orotate phosphoribosyltransferase, a potential target for antimalarial drugs and a conduit for prodrugs, crystallized as a structure with eight molecules per asymmetric unit that included some unique parasite-specific auto-inhibitory interactions between catalytic dimers.


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Superoxide dismutases (SODs) catalyze the conversion of superoxide to molecular oxygen, thus protecting organisms against toxic radicals. Iron-dependent SODs from T. cruzi, L. major and B. bovis exist as multiple isoforms with distinct structural features.
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