4ZCS

Crystal structure of the C-terminal catalytic domain of Plasmodium falciparum CTP:phosphocholine cytidylyltransferase in complex with CDP-choline

Summary for 4ZCS

• Entry DOI: 10.2210/pdb4zcs/pdb
• Related: 4ZCP 4ZCQ 4ZCR
• Descriptor: Choline-phosphate cytidylyltransferase, [2-CYTIDYLATE-O'-PHOSPHONYLOXYL]-ETHYL-TRIMETHYL-AMMONIUM, 3,6,9,12,15,18-HEXAOXAICOSANE-1,20-DIOL, ... (4 entities in total)
• Functional Keywords: enzyme, malaria, cytidylyltransferase, phosphatidylcholine, transferase
• Biological source: Plasmodium falciparum (isolate 3D7)
• Total number of polymer chains: 6
• Total formula weight: 128443.45

Authors

Guca, E.,Hoh, F.,Guichou, J.-F.,Cerdan, R. (deposition date: 2015-04-16, release date: 2016-08-17, Last modification date: 2024-01-10)

Primary citation

Guca, E.,Nagy, G.N.,Hajdu, F.,Marton, L.,Izrael, R.,Hoh, F.,Yang, Y.,Vial, H.,Vertessy, B.G.,Guichou, J.F.,Cerdan, R.
Structural determinants of the catalytic mechanism of Plasmodium CCT, a key enzyme of malaria lipid biosynthesis.
Sci Rep, 8:11215-11215, 2018

PubMed Abstract: The development of the malaria parasite, Plasmodium falciparum, in the human erythrocyte, relies on phospholipid metabolism to fulfil the massive need for membrane biogenesis. Phosphatidylcholine (PC) is the most abundant phospholipid in Plasmodium membranes. PC biosynthesis is mainly ensured by the de novo Kennedy pathway that is considered as an antimalarial drug target. The CTP:phosphocholine cytidylyltransferase (CCT) catalyses the rate-limiting step of the Kennedy pathway. Here we report a series of structural snapshots of the PfCCT catalytic domain in its free, substrate- and product-complexed states that demonstrate the conformational changes during the catalytic mechanism. Structural data show the ligand-dependent conformational variations of a flexible lysine. Combined kinetic and ligand-binding analyses confirm the catalytic roles of this lysine and of two threonine residues of the helix αE. Finally, we assessed the variations in active site residues between Plasmodium and mammalian CCT which could be exploited for future antimalarial drug design.

PubMed: 30046154
DOI: 10.1038/s41598-018-29500-9

Experimental method

X-RAY DIFFRACTION (2.45 Å)