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Originally published In Press as doi:10.1074/jbc.M007531200 on October 26, 2000

J. Biol. Chem., Vol. 276, Issue 8, 5959-5966, February 23, 2001
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Crystal Structure of the Iron-dependent Regulator from Mycobacterium tuberculosis at 2.0-Å Resolution Reveals the Src Homology Domain 3-like Fold and Metal Binding Function of the Third Domain*

Michael D. FeeseDagger §, Bjarni Pàll Ingason§, Joanne Goranson-Siekierke||, Randall K. Holmes||, and Wim G. J. HolDagger §**Dagger Dagger

From the Departments of Dagger  Biological Structure and  Biochemistry, § Biomolecular Structure Center, and ** Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, and the || Department of Microbiology, University of Colorado Health Sciences Center, Denver, Colorado 80262

Iron-dependent regulators are primary transcriptional regulators of virulence factors and iron scavenging systems that are important for infection by several bacterial pathogens. Here we present the 2.0-Å crystal structure of the wild type iron-dependent regulator from Mycobacterium tuberculosis in its fully active holorepressor conformation. Clear, unbiased electron density for the Src homology domain 3-like third domain, which is often invisible in structures of iron-dependent regulators, was revealed by density modification and averaging. This domain is one of the rare examples of Src homology domain 3-like folds in bacterial proteins, and, in addition, displays a metal binding function by contributing two ligands, one Glu and one Gln, to the pentacoordinated cobalt atom at metal site 1. Both metal sites are fully occupied, and tightly bound water molecules at metal site 1 ("Water 1") and metal site 2 ("Water 2") are identified unambiguously. The main chain carbonyl of Leu4 makes an indirect interaction with the cobalt atom at metal site 2 via Water 2, and the adjacent residue, Val5, forms a rare gamma  turn. Residues 1-3 are well ordered and make numerous interactions. These ordered solvent molecules and the conformation and interactions of the N-terminal pentapeptide thus might be important in metal-dependent activation.

* This work was supported by National Institutes of Health Grants R01CA65656 (to W. G. J. H.) and R01AI14107 (to R. K. H.) and by a major equipment grant from the Murdock Charitable Trust (to the Biomolecular Structure Center at the University of Washington).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The atomic coordinates and the structure factors (code 1fx7) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

Dagger Dagger To whom correspondence should be addressed. E-mail: hol@gouda.bmsc.washington.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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