Structures stabilizing the dimer interface on human 11 beta-hydroxysteroid dehydrogenase types 1 and 2 and human 15-hydroxyprostaglandin dehydrogenase and their homologs.
Human 11 beta-hydroxysteroid dehydrogenase-types 1 and 2 and human 15-hydroxyprostaglandin dehydrogenase belong to a large family of oxidoreductases that includes human dihydropteridine reductase and Streptomyces hydrogenans 20 beta-hydroxysteroid dehydrogenase, for which 3D structures are available. Almost all of these enzymes are either dimers or tetramers. The dimer interface of rat dihydropteridine reductase consists of alpha-helices E and F from each monomer arranged in a four alpha-helix bundle [Varughese et al. (1992) Proc. Natl. Acad. Sci. USA 89, 6080-6084]. Alpha-helix F contains tyrosine-146 and lysine-150, residues that are highly conserved in this protein superfamily and have been proposed to be at the catalytic site. We have examined the dimer interface between alpha-helix F in human and rat dihydropteridine reductase and Streptomyces hydrogenans 20 beta-hydroxysteroid dehydrogenase as well as modeled 3D structures of steroid and prostaglandin dehydrogenases and homologs for stabilizing interactions. We find a site in the middle of alpha-helix F that stabilizes the dimer. This anchor is adjacent to conserved lysine on alpha-helix F. Our analysis suggests that sequence variation in the anchor may be important in substrate specificity.
Tsigelny
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Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla 92093, USA.
Baker
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ME
D042842:11-beta-Hydroxysteroid Dehydrogenases; D000595:Amino Acid Sequence; D000818:Animals; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000737:chemistry*; D006913:Hydroxysteroid Dehydrogenases / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D051381:Rats; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013302:Streptomyces / Q000201:enzymology; D013329:Structure-Activity Relationship
D006913:Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; D042842:11-beta-Hydroxysteroid Dehydrogenases