Targeting Plasmodium PI(4)K to eliminate malaria

McNamara, Case W.; Lee, Marcus; Lim, Chek Shik; Lim, Shimin; Roland, Jason; Simon, Oliver; Yeung, Bryan K. S.; Chatterjee, Arnab K.; McCormack, Susan; Manary, Micah J; Zeeman, Anne‐Marie; Dechering, Koen J.; Kumar, Tr Santha; Henrich, Philipp P.; Gagaring, Kerstin; Ibanez, Maureen; Kato, Nobutaka; Kuhen, Kelli; Fischli, Christoph; Nagle, A. S.; Rottmann, Matthias; Plouffe, David; Bursulaya, Badry; Meister, Stephan; Rameh, Lucia E.; Trappe, Joerg; Haasen, Dorothea; Timmerman, Martijn; Sauerwein, Robert W.; Suwanarusk, Rossarin; Russell, Bruce; Rénia, Laurent; Nosten, François; Tully, David C.; Kocken, Clemens H. M.; Glynne, Richard; Bodenreider, Christophe; Fidock, David A.; Diagana, Thierry T.; Winzeler, Elizabeth A.

doi:10.1038/nature12782

Cited by 384 publications

(477 citation statements)

References 47 publications

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“…7(B,C)]. The compound BQR695 is a recently reported highly potent PI4KIIIβ inhibitor that has high potency against both the human (IC50 = 80 n M ) and Plasmodium vivax (∼3.5 n M ) variants of PI4KIIIβ 26. The binding mode of this compound was unambiguous (Supporting Information Fig.…”

Section: Resultsmentioning

confidence: 97%

“…Herein we describe an experimental approach to use HDX‐MS to define dynamic regions within a protein complex, in this case the type III phosphatidylinositol 4 kinase beta (PI4KIIIβ) in complex with the GTPase Rab11, and use this information to generate optimized constructs for X‐ray crystallography. PI4KIIIβ is a lipid kinase that plays a key role in mediating membrane trafficking,21 and is also an emerging drug target for both antiviral22, 23, 24, 25 and antimalarial therapeutics 26. The combined HDX‐MS and X‐ray crystallographic analysis reveals novel aspects of the PI4KIIIβ‐Rab11 complex, specifically conformational changes induced in the switch regions of activated Rab11, as well as novel molecular details of PI4K inhibitor interactions.…”

Section: Introductionmentioning

confidence: 99%

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Using hydrogen deuterium exchange mass spectrometry to engineer optimized constructs for crystallization of protein complexes: Case study of PI4KIIIβ with Rab11

et al. 2016

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The ability of proteins to bind and interact with protein partners plays fundamental roles in many cellular contexts. X‐ray crystallography has been a powerful approach to understand protein‐protein interactions; however, a challenge in the crystallization of proteins and their complexes is the presence of intrinsically disordered regions. In this article, we describe an application of hydrogen deuterium exchange mass spectrometry (HDX‐MS) to identify dynamic regions within type III phosphatidylinositol 4 kinase beta (PI4KIIIβ) in complex with the GTPase Rab11. This information was then used to design deletions that allowed for the production of diffraction quality crystals. Importantly, we also used HDX‐MS to verify that the new construct was properly folded, consistent with it being catalytically and functionally active. Structures of PI4KIIIβ in an Apo state and bound to the potent inhibitor BQR695 in complex with both GTPγS and GDP loaded Rab11 were determined. This hybrid HDX‐MS/crystallographic strategy revealed novel aspects of the PI4KIIIβ‐Rab11 complex, as well as the molecular mechanism of potency of a PI4K specific inhibitor (BQR695). This approach is widely applicable to protein‐protein complexes, and is an excellent strategy to optimize constructs for high‐resolution structural approaches.

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Section: Resultsmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Using hydrogen deuterium exchange mass spectrometry to engineer optimized constructs for crystallization of protein complexes: Case study of PI4KIIIβ with Rab11

et al. 2016

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“…Our in silico studies lead to the identification of proteins containing PIPbinding FYVE (22) or PH domains 6 . One of the PH domaincontaining proteins possessed a protein kinase domain and an N-terminal EF-hand calcium-binding motif (Fig.…”

Section: Resultsmentioning

confidence: 99%

Regulation of Plasmodium falciparum Development by Calcium-dependent Protein Kinase 7 (PfCDPK7)

Kumar

Tripathi

Ranjan

et al. 2014

Journal of Biological Chemistry

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Background: Calcium-dependent protein kinase (CDPK) regulate key processes in malaria parasite. However, the role of PfCDPK7 has remained unclear. Results: PfCDPK7 is an effector of PI(4,5)P 2 and regulates key parasitic processes. Conclusion: PfCDPK7 is a target of PI(4,5)P 2 and is critical for parasite development. Significance: The data provides novel insights into the role of PfCDPK7, a key kinase of P. falciparum.

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“…Interestingly, PF3D7_1129600 catalyzes the phosphorylation of phosphatidylinositol 4-phosphate to form phosphatidylinositol 4,5-bisphosphate (30). The drug target PI(4)K (PF3D7_0509800) alters the intracellular distribution of phosphatidylinositol-4-phosphate in the parasite, placing these genes on the same biologic pathway (31). Although the functional significance of this signal is unclear, genome scans in other populations also have identified strong directional selection at this locus (27,32).…”

Section: P Vivax Shows Stronger Evidence Of Recent Directional Selecmentioning

confidence: 99%

Selective sweep suggests transcriptional regulation may underlie Plasmodium vivax resilience to malaria control measures in Cambodia

Parobek

Lin

Saunders

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Cambodia, in which both Plasmodium vivax and Plasmodium falciparum are endemic, has been the focus of numerous malaria-control interventions, resulting in a marked decline in overall malaria incidence. Despite this decline, the number of P. vivax cases has actually increased. To understand better the factors underlying this resilience, we compared the genetic responses of the two species to recent selective pressures. We sequenced and studied the genomes of 70 P. vivax and 80 P. falciparum isolates collected between 2009 and 2013. We found that although P. falciparum has undergone population fracturing, the coendemic P. vivax population has grown undisrupted, resulting in a larger effective population size, no discernable population structure, and frequent multiclonal infections. Signatures of selection suggest recent, species-specific evolutionary differences. Particularly, in contrast to P. falciparum, P. vivax transcription factors, chromatin modifiers, and histone deacetylases have undergone strong directional selection, including a particularly strong selective sweep at an AP2 transcription factor. Together, our findings point to different population-level adaptive mechanisms used by P. vivax and P. falciparum parasites. Although population substructuring in P. falciparum has resulted in clonal outgrowths of resistant parasites, P. vivax may use a nuanced transcriptional regulatory approach to population maintenance, enabling it to preserve a larger, more diverse population better suited to facing selective threats. We conclude that transcriptional control may underlie P. vivax's resilience to malaria control measures. Novel strategies to target such processes are likely required to eradicate P. vivax and achieve malaria elimination.D uring the last decade, western Cambodia has been the focus of numerous and multimodal interventions to control the spread of artemisinin-resistant Plasmodium falciparum (1, 2). Such interventions, including increased vector control, increased surveillance, and improved access to quality artemisinin-combination therapy (ACT), would be expected to curtail coendemic Plasmodium vivax as well. However, even as P. falciparum infections in Cambodia decreased by 81% between 2009 and 2013, P. vivax cases have increased, making it the predominant species in the Mekong region (3-6). This scenario, repeated in Brazil and other areas of coendemicity, has led to growing awareness that P. vivax, although infecting the same populations and transmitted by the same mosquito vectors, will likely be the more challenging species to eradicate (6-9). In this study, we use population genomics to gain insight into the evolutionary factors underlying P. vivax's resilience to malaria control measures.Population genetic studies have previously hinted at the resilience of P. vivax populations in comparison with P. falciparum. Studies of microsatellites and highly variable antigens of sympatric P. vivax and P. falciparum populations in Southeast Asia and the Southwest Pacific have consistently shown P. viv...

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Targeting Plasmodium PI(4)K to eliminate malaria

Cited by 384 publications

References 47 publications

Using hydrogen deuterium exchange mass spectrometry to engineer optimized constructs for crystallization of protein complexes: Case study of PI4KIIIβ with Rab11

Using hydrogen deuterium exchange mass spectrometry to engineer optimized constructs for crystallization of protein complexes: Case study of PI4KIIIβ with Rab11

Regulation of Plasmodium falciparum Development by Calcium-dependent Protein Kinase 7 (PfCDPK7)

Selective sweep suggests transcriptional regulation may underlie Plasmodium vivax resilience to malaria control measures in Cambodia

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