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Abstract
The gene for human hydroxysteroid sulfotransferase (SULT2B1) encodes two peptides, SULT2B1a and SULT2B1b, that differ only at their amino termini. SULT2B1b has a predilection for cholesterol but is also capable of sulfonating pregnenolone, whereas SULT2B1a preferentially sulfonates pregnenolone and only minimally sulfonates cholesterol. We have determined the crystal structure of SULT2B1a and SULT2B1b bound to the substrate donor product 3'-phosphoadenosine 5'-phosphate at 2.9 and 2.4 A, respectively, as well as SULT2B1b in the presence of the acceptor substrate pregnenolone at 2.3 A. These structures reveal a different catalytic binding orientation for the substrate from a previously determined structure of hydroxysteroid sulfotransferase (SULT2A1) binding dehydroepiandrosterone. In addition, the amino-terminal helix comprising residues Asp19 to Lys26, which determines the specificity difference between the SULT2B1 isoforms, becomes ordered upon pregnenolone binding, covering the substrate binding pocket.
Highlights
From the ‡Laboratory of Structural Biology and the §Pharmacogenetic Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, and the ¶Section on Steroid Regulation, Endocrinology and Reproduction Research Branch, NICHD, National Institutes of Health, Bethesda, Maryland 20892-4510
Previous studies showed that removal of the 52 amino acid carboxyl-terminal end that is common to both SULT2B1 isoforms has no effect on catalytic activity of either isoform [5]
Removal of the 8-residue aminoterminal end that is unique to SULT2B1a has no significant effect on catalytic activity; removal of the 23-residue amino-terminal end that is unique to SULT2B1b abolishes catalytic activity for cholesterol but not pregnenolone [5]
Summary
44593–44599, 2003 Printed in U.S.A. Crystal Structure of Human Cholesterol Sulfotransferase (SULT2B1b) in the Presence of Pregnenolone and 3-Phosphoadenosine 5-Phosphate. The gene for human hydroxysteroid sulfotransferase (SULT2B1) encodes two peptides, SULT2B1a and SULT2B1b, that differ only at their amino termini. We have determined the crystal structure of SULT2B1a and SULT2B1b bound to the substrate donor product 3-phosphoadenosine 5-phosphate at 2.9 and 2.4 Å, respectively, as well as SULT2B1b in the presence of the acceptor substrate pregnenolone at 2.3 Å These structures reveal a different catalytic binding orientation for the substrate from a previously determined structure of hydroxysteroid sulfotransferase (SULT2A1) binding dehydroepiandrosterone. Two human hydroxysteroid sulfotransferases, SULT2B1a and SULT2B1b, have been shown to be encoded by the same gene but differ at the amino terminus by 8 and 23 amino acids, respectively, as a result of an alternative exon 1 [4].
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