Journal article
Crystal Structures of the carboxyl cGMP Binding Domain of the Plasmodium falciparum cGMP-dependent Protein Kinase Reveal a Novel Capping Triad Crucial for Merozoite Egress

Publication Details
Kim, J.; Flueck, C.; Franz, E.; Sanabria-Figueroa, E.; Thompson, E.; Lorenz, R.; Bertinetti, D.; Baker, D.; Herberg, F.; Kim, C.
Publication year:
PLoS Pathogens
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The Plasmodium falciparum cGMP-dependent protein kinase (PfPKG) is a key regulator across the malaria parasite life cycle. Little is known about PfPKG’s activation mechanism. Here we report that the fourth cyclic nucleotide binding domain functions as a “gatekeeper” for activation by providing the highest cGMP affinity and selectivity. To understand the mechanism, we have solved its crystal structures with and without cGMP at 2.0 and 1.9 Å. These structures revealed a PfPKG-specific capping triad that dynamically forms upon cGMP binding and disrupting the triad reduces 90 % of the kinase activity. Furthermore, mutating these residues in the parasite prevents blood stage merozoite egress, confirming the essential nature of the triad in the parasite. We propose a mechanism of activation where cGMP binding allosterically triggers the conformational change at the αC-helix, which bridges the regulatory and catalytic domains, causing the capping triad to form and stabilize the active conformation.

Last updated on 2019-01-11 at 16:05