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J. Biol. Chem., Vol. 279, Issue 43, 45185-45193, October 22, 2004

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Structural Analysis of the Sulfotransferase (3-O-Sulfotransferase Isoform 3) Involved in the Biosynthesis of an Entry Receptor for Herpes Simplex Virus 1^*

Andrea F. Moon, Suzanne C. Edavettal, Joe M. Krahn, Eva M. Munoz¶, Masahiko Negishi||, Robert J. Linhardt¶, Jian Liu**, and Lars C. Pedersen

From the Laboratories of Structural Biology and ^||Reproductive and Developmental Toxicology, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709, the Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, and the ^¶Department of Chemistry and Chemical Biology, Rensselaer Polytechnic Institute, Troy, New York 12180

Heparan sulfate (HS) plays essential roles in assisting herpes simplex virus infection and other biological processes. The biosynthesis of HS includes numerous specialized sulfotransferases that generate a variety of sulfated saccharide sequences, conferring the selectivity of biological functions of HS. We report a structural study of human HS 3-O-sulfotransferase isoform 3 (3-OST-3), a key sulfotransferase that transfers a sulfuryl group to a specific glucosamine in HS generating an entry receptor for herpes simplex virus 1. We have obtained the crystal structure of 3-OST-3 at 1.95 Å in a ternary complex with 3'-phosphoadenosine 5'-phosphate and a tetrasaccharide substrate. Mutational analyses were also performed on the residues involved in the binding of the substrate. Residues Gln²⁵⁵ and Lys³⁶⁸ are essential for the sulfotransferase activity and lie within hydrogen bonding distances to the carboxyl and sulfo groups of the uronic acid unit. These residues participate in the substrate recognition of 3-OST-3. This structure provides atomic level evidence for delineating the substrate recognition and catalytic mechanism for 3-OST-3.

Received for publication, May 5, 2004 , and in revised form, August 3, 2004.

The atomic coordinates and structure factors (codes 1T8U and 1T8T) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work is supported in part by National Institutes of Health Grants AI50050 (to J. L.) and HL52622 (to R. J. L.) and Grant-in-Aid 0355800U (to J. L.) from the American Heart Association MidAtlantic Affiliate. 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.

^** To whom correspondence should be addressed: Rm. 309, Beard Hall, University of North Carolina, Chapel Hill, NC 27599. Tel.: 919-843-6511; Fax: 919-843-5432; E-mail: jian_liu{at}unc.edu.

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