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J. Biol. Chem., Vol. 282, Issue 13, 9914-9922, March 30, 2007

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Crystal Structure and Function of the Zinc Uptake Regulator FurB from Mycobacterium tuberculosis^*

Debora Lucarelli, Santina Russo^||, Elspeth Garman^¶, Anna Milano, Wolfram Meyer-Klaucke¹, and Ehmke Pohl^||2

From the European Molecular Biology Laboratory, Hamburg Outstation, Notkestrasse 85, D-22603 Hamburg, Germany, ^¶Laboratory of Molecular Biophysics, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom, the Department of Genetics and Microbiology, University of Pavia, 27100 Pavia, Italy, and ^||Swiss Light Source, Paul Scherrer Institut, CH-5232 Villigen, Switzerland

Members of the ferric/zinc uptake regulator (Fur/Zur) family are the central metal-dependent regulator proteins in many Gram-negative and -positive bacteria. They are responsible for the control of a wide variety of basic physiological processes and the expression of important virulence factors in human pathogens. Therefore, Fur has gathered significant interest as a potential target for novel antibiotics. Here we report the crystal structure of FurB from Mycobacterium tuberculosis at a resolution of 2.7Å, and we present biochemical and spectroscopic data that allow us to propose the functional role of this protein. Although the overall fold of FurB with an N-terminal DNA binding domain and a C-terminal dimerization domain is conserved among the Zur/Fur family, large differences in the spatial arrangement of the two domains with respect to each other can be observed. The biochemical and spectroscopic analysis presented here reveals that M. tuberculosis FurB is Zn(II)-dependent and is likely to control genes involved in the bacterial zinc uptake. The combination of the structural, spectroscopic, and biochemical results enables us to determine the structural basis for functional differences in this important family of bacterial regulators.

Received for publication, October 24, 2006 , and in revised form, January 9, 2007.

The atomic coordinates and structure factors (code 2O03) 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 a short term fellowship (to D. L.) from the Boehringer Ingelheim Fonds, by the EU-VI framework Contract LSHP-CT-2005-018923, and by subcontract (to E. P.) from NIAID Grant AI15940 from the National Institutes of Health. 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.

¹ To whom correspondence regarding spectroscopy should be addressed. E-mail: wolfram{at}embl-hamburg.de. ² To whom correspondence should be addressed. E-mail: ehmke.pohl{at}psi.ch.

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