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Published online before print March 9, 2004, 10.1110/ps.03456404
Protein Science (2004), 13:1155-1163. Published by Cold Spring Harbor Laboratory Press. Copyright © 2004 The Protein Society
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FOR THE RECORD

An improved crystal form of Plasmodium falciparum peptide deformylase

Mark A. Robien1, Kiet T. Nguyen3, Abhinav Kumar1,2,4, Irwin Hirsh1,2,5, Stewart Turley1,2, Dehua Pei3 and Wim G.J. Hol1,2

1 Department of Biochemistry and
2 Howard Hughes Medical Institute, Biomolecular Structure Center, University of Washington, Seattle, Washington 98195, USA
3 Department of Chemistry and Ohio State Biochemistry Program, The Ohio State University, Columbus, Ohio 43210, USA

(RECEIVED September 24, 2003; FINAL REVISION November 6, 2003; ACCEPTED November 7, 2003)



Abstract

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 Å resolution, an improvement over the 2.8 Å 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.

Keywords: crystal engineering; drug design; malaria; PDF; Plasmodium

Reprint requests to: Wim G.J. Hol, Box 357742, University of Washington, Seattle, Washington 98195, USA; e-mail: wghol{at}u.washington.edu; fax: (206) 685-7002.

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.03456404.

4 Present addresses: Plexxikon, Inc., Berkeley, CA 94710, USA;

5 Amersham Biosciences, Fast Trak, Uppsala, Sweden 751 84.


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