Crystals of peptide deformylase from Plasmodium falciparum reveal critical characteristics of the active site for drug design.
Peptide deformylase catalyzes the deformylation reaction of the amino terminal fMet residue of newly synthesized proteins in bacteria, and most likely in Plasmodium falciparum, and has therefore been identified as a potential antibacterial and antimalarial drug target. The structure of P. falciparum peptide deformylase, determined at 2.8 A resolution with ten subunits per asymmetric unit, is similar to the bacterial enzyme with the residues involved in catalysis, the position of the bound metal ion, and a catalytically important water structurally conserved between the two enzymes. However, critical differences in the substrate binding region explain the poor affinity of E. coli deformylase inhibitors and substrates toward the Plasmodium enzyme. The Plasmodium structure serves as a guide for designing novel antimalarials.
Kumar
Abhinav
A
Howard Hughes Medical Institute, University of Washington, Seattle 98195, USA.
Nguyen
Kiet T
KT
Srivathsan
Sumant
S
Ornstein
Brad
B
Turley
Stewart
S
Hirsh
Irwin
I
Pei
Dehua
D
Hol
Wim G J
WG
D000581:Amidohydrolases; D000595:Amino Acid Sequence; D000626:Aminopeptidases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000962:Antimalarials; D001665:Binding Sites; D002384:Catalysis; D003035:Cobalt / Q000378:metabolism; D003460:Crystallization; D018360:Crystallography, X-Ray; D015195:Drug Design; D004926:Escherichia coli / Q000201:enzymology; D006801:Humans; D008667:Metalloproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000201:enzymology*; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D021122:Protein Subunits; D016415:Sequence Alignment
D000962:Antimalarials; D008667:Metalloproteins; D021122:Protein Subunits; D003035:Cobalt; D000626:Aminopeptidases; D000581:Amidohydrolases; C084507:peptide deformylase