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J. Biol. Chem., Vol. 279, Issue 19, 20480-20489, May 7, 2004

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Crystal Structure of Human Thimet Oligopeptidase Provides Insight into Substrate Recognition, Regulation, and Localization^*

Kallol Ray, Christina S. Hines, Jerry Coll-Rodriguez, and David W. Rodgers¶

From the Department of Molecular and Cellular Biochemistry and Center for Structural Biology, University of Kentucky, Lexington, Kentucky 40536

Thimet oligopeptidase (TOP) is a zinc metallopeptidase that metabolizes a number of bioactive peptides and degrades peptides released by the proteasome, limiting antigenic presentation by MHC class I molecules. We present the crystal structure of human TOP at 2.0-Å resolution. The active site is located at the base of a deep channel that runs the length of the elongated molecule, an overall fold first seen in the closely related metallopeptidase neurolysin. Comparison of the two related structures indicates hinge-like flexibility and identifies elements near one end of the channel that adopt different conformations. Relatively few of the sequence differences between TOP and neurolysin map to the proposed substrate-binding site, and four of these variable residues may account for differences in substrate specificity. In addition, a loop segment (residues 599-611) in TOP differs in conformation and degree of order from the corresponding neurolysin loop, suggesting it may also play a role in activity differences. Cysteines thought to mediate covalent oligomerization of rat TOP, which can inactivate the enzyme, are found to be surface-accessible in the human enzyme, and additional cysteines (residues 321,350, and 644) may also mediate multimerization in the human homolog. Disorder in the N terminus of TOP indicates it may be involved in subcellular localization, but a potential nuclear import element is found to be part of a helix and, therefore, unlikely to be involved in transport. A large acidic patch on the surface could potentially mediate a protein-protein interaction, possibly through formation of a covalent linkage.

Received for publication, January 23, 2004 , and in revised form, February 27, 2004.

The atomic coordinates and structure factors (code 1S4B) 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 United States Public Health Service Grant NS38041 (to D. W. R.), National Science Foundation Grant MCB-9904886 (to D. W. R.), and American Chemical Society Petroleum Research Fund 37135-AC4 (to D. W. R.). 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.

A predoctoral fellow of the American Heart Association Ohio Valley Affiliate.

A fellow of the National Institute on Drug Abuse (Grant DA14596).

^¶ To whom correspondence should be addressed. Tel.: 859-257-5205; Fax: 859-323-1037; E-mail: david.rodgers{at}uky.edu.

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