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Lookup NU author(s): Professor Martin NobleORCiD, Professor Jane Endicott
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Malaria is a major threat to world health. The identification of parasite targets for drug development is a priority and parasitic protein kinases suggest themselves as suitable targets as many display profound structural and functional divergences from their host counterparts. In this paper, we describe the structure of the orphan protein kinase, Plasmodium falciparum protein kinase 7 (PFPK7). Several Plasmodium protein kinases contain extensive insertions, and the structure of PFPK7 reveals how these may be accommodated as excursions from the canonical eukaryotic protein kinase fold. The constitutively active conformation of PFPK7 is stabilized by a structural motif in which the role of the conserved phosphorylated residue that assists in structuring the activation loop of many protein kinases is played by an arginine residue. We identify two series of PFPK7 ATP-competitive inhibitors and suggest further developments for the design of selective and potent PFPK7 lead compounds as potential antimalarials.
Author(s): Merckx A, Echalier A, Langford K, Sicard A, Langsley G, Joore J, Doerig C, Noble M, Endicott J
Publication type: Article
Publication status: Published
Journal: Structure
Year: 2008
Volume: 16
Issue: 2
Pages: 228-238
ISSN (print): 0969-2126
ISSN (electronic): 1878-4186
Publisher: Cell Press
URL: http://dx.doi.org/10.1016/j.str.2007.11.014
DOI: 10.1016/j.str.2007.11.014
PubMed id: 18275814
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