An improved crystal form of Plasmodium falciparum peptide deformylase.
An altered version of peptide deformylase from Plasmodium falciparum (PfPDF), the organism that causes the most devastating form of malaria, has been cocrystallized with a synthesized inhibitor that has submicromolar affinity for its target protein. The structure is solved at 2.2 A resolution, an improvement over the 2.8 A resolution achieved during the structural determination of unliganded PfPDF. This represents the successful outcome of modifying the protein construct in order to overcome adverse crystal contacts and other problems encountered in the study of unliganded PfPDF. Two molecules of PfPDF are found in the asymmetric unit of the current structure. The active site of each monomer of PfPDF is occupied by a proteolyzed fragment of the tripeptide-like inhibitor. Unexpectedly, each PfPDF subunit is associated with two nearly complete molecules of the inhibitor, found at a protein-protein interface. This is the first structure of a eukaryotic PDF protein, a potential drug target, in complex with a ligand.
Robien
Mark A
MA
University of Washington, Seattle, Washington 98195, USA.
Nguyen
Kiet T
KT
Kumar
Abhinav
A
Hirsh
Irwin
I
Turley
Stewart
S
Pei
Dehua
D
Hol
Wim G J
WG
D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D003460:Crystallization; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000737:chemistry / Q000201:enzymology*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism
D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D000581:Amidohydrolases; C084507:peptide deformylase