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J. Biol. Chem., Vol. 280, Issue 1, 484-493, January 7, 2005

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The 1.8-Å Crystal Structure of Human Tear Lipocalin Reveals an Extended Branched Cavity with Capacity for Multiple Ligands^*

Daniel A. Breustedt, Ingo P. Korndörfer, Bernhard Redl¶, and Arne Skerra||

From the Lehrstuhl für Biologische Chemie, Technische Universität München, D-85350 Freising-Weihenstephan, Germany and Institut für Molekularbiologie, Medizinische Universität Innsbruck, A-6020 Innsbruck, Austria

In contrast with earlier assumptions, which classified human tear lipocalin (Tlc) as an outlier member of the lipocalin protein family, the 1.8-Å resolution crystal structure of the recombinant apoprotein confirms the typical eight-stranded antiparallel -barrel architecture with an -helix attached to it. The fold of Tlc most closely resembles the bovine dander allergen Bos d 2, a well characterized prototypic lipocalin, but also reveals similarity with -lactoglobulin. However, compared with other lipocalin structures Tlc exhibits an extremely wide ligand pocket, whose entrance is formed by four partially disordered loops. The cavity deeply extends into the -barrel structure, where it ends in two distinct lobes. This unusual structural feature explains the known promiscuity of Tlc for various ligands, with chemical structures ranging from lipids and retinoids to the macrocyclic antibiotic rifampin and even to microbial siderophores. Notably, earlier findings of biological activity as a thiol protease inhibitor have no correspondence in the three-dimensional structure of Tlc, rather it appears that its proteolytic fragments could be responsible for this phenomenon. Hence, the present structural analysis sheds new light on the ligand binding activity of this functionally obscure but abundant human lipocalin.

Received for publication, September 13, 2004 , and in revised form, October 5, 2004.

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

^* 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.

^¶ Supported by Austrian Science Foundation (FWF) Grant P14850.

^|| To whom correspondence should be addressed: Lehrstuhl für Biologische Chemie, Technische Universität München, D-85350 Freising-Weihenstephan, Germany. Tel.: 49-8161-71-4351; Fax: 49-8161-71-4352; E-mail: skerra{at}wzw.tum.de.

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