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Crystal structure of PfRh5, an essential P. falciparum ligand for invasion of human erythrocytes.

Chen L, Xu Y, Healer J, Thompson JK, Smith BJ, Lawrence MC, Cowman AF - Elife (2014)

View Article: PubMed Central - PubMed

Affiliation: Division of Infection and Immunity, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.

ABSTRACT

Plasmodium falciparum causes the most severe form of malaria in humans and is responsible for over 700,000 deaths annually. It is an obligate intracellular parasite and invades erythrocytes where it grows in a relatively protected niche. Invasion of erythrocytes is essential for parasite survival and this involves interplay of multiple protein–protein interactions. One of the most important interactions is binding of parasite invasion ligand families EBLs and PfRhs to host receptors on the surface of erythrocytes. PfRh5 is the only essential invasion ligand within the PfRh family and is an important vaccine candidate. PfRh5 binds the host receptor basigin. In this study, we have determined the crystal structure of PfRh5 using diffraction data to 2.18 Å resolution. PfRh5 exhibits a novel fold, comprising nine mostly anti-parallel α-helices encasing an N-terminal β-hairpin, with the overall shape being an elliptical disk. This is the first three-dimensional structure determined for the PfRh family of proteins.

Doi:: http://dx.doi.org/10.7554/eLife.04187.001

No MeSH data available.


A unique pocket on the surface of the PfRh5 molecule.(A) Location of the pocket on the surface formed by the β-hairpin, the triple-helical bundle, and the triple-helical coiled coil. (B) Close-up view of the pocket; key residues lining the pocket are labeled.DOI:http://dx.doi.org/10.7554/eLife.04187.011
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fig2s4: A unique pocket on the surface of the PfRh5 molecule.(A) Location of the pocket on the surface formed by the β-hairpin, the triple-helical bundle, and the triple-helical coiled coil. (B) Close-up view of the pocket; key residues lining the pocket are labeled.DOI:http://dx.doi.org/10.7554/eLife.04187.011

Mentions: Analyses of molecular surface using DoGSiteScorer (Volkamer et al., 2012) detected a number of pockets of dimensions suitable for targeting with small molecules on the surface of the PfRh5 structure. These pockets arise from the relatively loose packing of the four constituent domains of the PfRh5. One of these (Figure 2—figure supplement 4A) is lined by residues of mixed hydrophilicity and has a surface area of ∼430 Å2, of which ∼60% is lipophilic (Figure 2—figure supplement 4B). If this pocket is in proximity to the basigin binding site, small molecules targeting it may have the potential to interfere the interaction between the two molecules, either through disrupting the relatively loose packing of the constituent domains of PfRh5 or through steric interference. Alternatively, as PfRh5 functions in complex with PfRipr and at least one further parasite protein (Chen et al., 2011), if this pocket is involved in binding these partner/s, a small molecule targeting this pocket may likewise interfere with the complex formation and therefore ultimately with its function.


Crystal structure of PfRh5, an essential P. falciparum ligand for invasion of human erythrocytes.

Chen L, Xu Y, Healer J, Thompson JK, Smith BJ, Lawrence MC, Cowman AF - Elife (2014)

A unique pocket on the surface of the PfRh5 molecule.(A) Location of the pocket on the surface formed by the β-hairpin, the triple-helical bundle, and the triple-helical coiled coil. (B) Close-up view of the pocket; key residues lining the pocket are labeled.DOI:http://dx.doi.org/10.7554/eLife.04187.011
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4356141&req=5

fig2s4: A unique pocket on the surface of the PfRh5 molecule.(A) Location of the pocket on the surface formed by the β-hairpin, the triple-helical bundle, and the triple-helical coiled coil. (B) Close-up view of the pocket; key residues lining the pocket are labeled.DOI:http://dx.doi.org/10.7554/eLife.04187.011
Mentions: Analyses of molecular surface using DoGSiteScorer (Volkamer et al., 2012) detected a number of pockets of dimensions suitable for targeting with small molecules on the surface of the PfRh5 structure. These pockets arise from the relatively loose packing of the four constituent domains of the PfRh5. One of these (Figure 2—figure supplement 4A) is lined by residues of mixed hydrophilicity and has a surface area of ∼430 Å2, of which ∼60% is lipophilic (Figure 2—figure supplement 4B). If this pocket is in proximity to the basigin binding site, small molecules targeting it may have the potential to interfere the interaction between the two molecules, either through disrupting the relatively loose packing of the constituent domains of PfRh5 or through steric interference. Alternatively, as PfRh5 functions in complex with PfRipr and at least one further parasite protein (Chen et al., 2011), if this pocket is involved in binding these partner/s, a small molecule targeting this pocket may likewise interfere with the complex formation and therefore ultimately with its function.

View Article: PubMed Central - PubMed

Affiliation: Division of Infection and Immunity, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.

ABSTRACT

Plasmodium falciparum causes the most severe form of malaria in humans and is responsible for over 700,000 deaths annually. It is an obligate intracellular parasite and invades erythrocytes where it grows in a relatively protected niche. Invasion of erythrocytes is essential for parasite survival and this involves interplay of multiple protein–protein interactions. One of the most important interactions is binding of parasite invasion ligand families EBLs and PfRhs to host receptors on the surface of erythrocytes. PfRh5 is the only essential invasion ligand within the PfRh family and is an important vaccine candidate. PfRh5 binds the host receptor basigin. In this study, we have determined the crystal structure of PfRh5 using diffraction data to 2.18 Å resolution. PfRh5 exhibits a novel fold, comprising nine mostly anti-parallel α-helices encasing an N-terminal β-hairpin, with the overall shape being an elliptical disk. This is the first three-dimensional structure determined for the PfRh family of proteins.

Doi:: http://dx.doi.org/10.7554/eLife.04187.001

No MeSH data available.