Structure of bacterial 3beta/17beta-hydroxysteroid dehydrogenase at 1.2 A resolution: a model for multiple steroid recognition.
The enzyme 3beta/17beta-hydroxysteroid dehydrogenase (3beta/17beta-HSD) is a steroid-inducible component of the Gram-negative bacterium Comamonas testosteroni. It catalyzes the reversible reduction/dehydrogenation of the oxo/beta-hydroxy groups at positions 3 and 17 of steroid compounds, including hormones and isobile acids. Crystallographic analysis at 1.2 A resolution reveals the enzyme to have nearly identical subunits that form a tetramer with 222 symmetry. This is one of the largest oligomeric structures refined at this resolution. The subunit consists of a monomer with a single-domain structure built around a seven-stranded beta-sheet flanked by six alpha-helices. The active site contains a Ser-Tyr-Lys triad, typical for short-chain dehydrogenases/reductases (SDR). Despite their highly diverse substrate specificities, SDR members show a close to identical folding pattern architectures and a common catalytic mechanism. In contrast to other SDR apostructures determined, the substrate binding loop is well-defined. Analysis of structure-activity relationships of catalytic cleft residues, docking analysis of substrates and inhibitors, and accessible surface analysis explains how 3beta/17beta-HSD accommodates steroid substrates of different conformations.
Benach
Jordi
J
Karolinska Institutet NOVUM, Center for Structural Biochemistry, S-14157 Huddinge, Sweden.
Filling
Charlotta
C
Oppermann
Udo C T
UC
Roversi
Pietro
P
Bricogne
Gérard
G
Berndt
Kurt D
KD
Jörnvall
Hans
H
Ladenstein
Rudolf
R
D015067:17-Hydroxysteroid Dehydrogenases / Q000737:chemistry* / Q000235:genetics; D000728:Androgens / Q000737:chemistry; D001051:Apoenzymes / Q000737:chemistry / Q000235:genetics; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics; D001647:Bile Acids and Salts / Q000737:chemistry; D001665:Binding Sites / Q000235:genetics; D020604:Comamonas testosteroni / Q000201:enzymology* / Q000235:genetics; D018360:Crystallography, X-Ray; D004967:Estrogens / Q000737:chemistry; D008958:Models, Molecular; D017354:Point Mutation; D017510:Protein Folding; D017434:Protein Structure, Tertiary / Q000235:genetics; D013237:Stereoisomerism; D013379:Substrate Specificity / Q000235:genetics
D000728:Androgens; D001051:Apoenzymes; D001426:Bacterial Proteins; D001647:Bile Acids and Salts; D004967:Estrogens; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase