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J. Biol. Chem., Vol. 281, Issue 5, 2893-2900, February 3, 2006

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Enacyloxin IIa Pinpoints a Binding Pocket of Elongation Factor Tu for Development of Novel Antibiotics^*

Andrea Parmeggiani¹, Ivo M. Krab^¶2, Toshihiko Watanabe^||, Rikke C. Nielsen, Caroline Dahlberg³, Jens Nyborg, and Poul Nissen⁴

From the Department of Molecular Biology, University of Aarhus, Gustav Wieds Vej 10 C, DK-8000 Aarhus C, Denmark, Laboratoire de Biophysique, Ecole Polytechnique, F-91128 Palaiseau Cedex, France, ^¶Department of Chemistry, Leiden University, P.O. Box 9502, NL-2300 RA Leiden, The Netherlands, and ^||Department of Civil Engineering, Tohoku Institute of Technology, Sendai 982-8577, Japan

Elongation factor (EF-) Tu·GTP is the carrier of aminoacyl-tRNA to the programmed ribosome. Enacyloxin IIa inhibits bacterial protein synthesis by hindering the release of EF-Tu·GDP from the ribosome. The crystal structure of the Escherichia coli EF-Tu·guanylyl iminodiphosphate (GDPNP)·enacyloxin IIa complex at 2.3 Å resolution presented here reveals the location of the antibiotic at the interface of domains 1 and 3. The binding site overlaps that of kirromycin, an antibiotic with a structure that is unrelated to enacyloxin IIa but that also inhibits EF-Tu·GDP release. As one of the major differences, the enacyloxin IIa tail borders a hydrophobic pocket that is occupied by the longer tail of kirromycin, explaining the higher binding affinity of the latter. EF-Tu·GDPNP·enacyloxin IIa shows a disordered effector region that in the Phe-tRNA^Phe·EF-Tu (Thermus aquaticus)·GDPNP·enacyloxin IIa complex, solved at 3.1 Å resolution, is stabilized by the interaction with tRNA. This work clarifies the structural background of the action of enacyloxin IIa and compares its properties with those of kirromycin, opening new perspectives for structure-guided design of novel antibiotics.

Received for publication, June 1, 2005 , and in revised form, July 25, 2005.

The atomic coordinates and structure factors (code 2BVN and 1OB5) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by an Ole Rømer stipend, the Dansync Project of the Danish Natural Science Research Council, European Union Contract QLK2-CT-2002-00892, Grant 21-03-0214 from the Danish Natural Science Research Councils Centre for Structural Biology, and the European Molecular Biology Organization Young Investigator program. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental material.

² Present address: Molecular Biosciences and Bioengineering, University of Hawaii at Manoa, 1955 East-West Rd., Ag. Sci. 218, Honolulu, HI 96822-2321.

³ Present address: Dept. of Biochemistry, University of Washington, Box 357350, Seattle, WA 98195-7350.

¹ To whom correspondence may be addressed: Dept. of Molecular Biology, University of Aarhus, Gustav Wieds Vej 10 C, DK-8000 Aarhus C, Denmark. Tel.: 45-8942-5258; Fax: 45-8612-3178; E-mail: andrea{at}bioxray.dk.

⁴ To whom correspondence may be addressed. Tel.: 45-8942-5025; Fax: 45 8612 3178; E-mail: pn{at}mb.au.dk.

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