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J. Biol. Chem., Vol. 281, Issue 10, 6520-6527, March 10, 2006

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Crystal Structure of the Human B-form Low Molecular Weight Phosphotyrosyl Phosphatase at 1.6-Å Resolution^*

Adam P. R. Zabell, Alfred D. Schroff, Jr.^¶, Bornadata Evans Bain^¶, Robert L. Van Etten^¶, Olaf Wiest, and Cynthia V. Stauffacher¹

From the Department of Biological Sciences and the Purdue Cancer Center, Purdue University, West Lafayette, Indiana 47907-1392, the ^¶Department of Chemistry and the Purdue Cancer Center, Purdue University, West Lafayette, Indiana 47907-2084, and the Department of Chemistry and Biochemistry and the Walther Cancer Institute, University of Notre Dame, Notre Dame, Indiana 46556-5670

The crystal structure of HPTP-B, a human isoenzyme of the low molecular weight phosphotyrosyl phosphatase (LMW PTPase) is reported here at a resolution of 1.6 Å. This high resolution structure of the second human LMW PTPase isoenzyme provides the opportunity to examine the structural basis of different substrate and inhibitor/activator responses. The crystal packing of HPTP-B positions a normally surface-exposed arginine in a position equivalent to the tyrosyl substrate. A comparison of all deposited crystallographic coordinates of these PTPases reveals three atomic positions within the active site cavity occupied by hydrogen bond donor or acceptor atoms on bound molecules, suggesting useful design elements for synthetic inhibitors. A selection of inhibitor and activator molecules as well as small molecule and peptide substrates were tested against each human isoenzyme. These results along with the crystal packing seen in HPTP-B suggest relevant sequence elements in the currently unknown target sequence.

Received for publication, June 9, 2005 , and in revised form, October 25, 2005.

The atomic coordinates and structure factors (code 1XWW) 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 National Cancer Institute Grant CA82673 (to C. V. S.), the Walther Cancer Institute at the University of Notre Dame, and Purdue Cancer Center Grant CA23568. Data collection at the Advanced Photon Source was assisted by Dr. Stephan Ginell, and supported by the United States Department of Energy, Office of Energy Research, under contract W-31-109-ENG-38. 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 should be addresed: Dept. of Biological Sciences, Purdue University, West Lafayette, IN 47907-1392. Tel.: 765-494-4937; Fax: 765-496-1189; E-mail: cstauffa{at}purdue.edu.

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