PDBsum entry 1bhs

Oxidoreductase

PDB id: 1bhs

Contents

Protein chain

284 a.a. *

Waters ×49

* Residue conservation analysis

PDB id:

1bhs

Name:

Oxidoreductase

Title:

Human estrogenic 17beta-hydroxysteroid dehydrogenase

Structure:

17beta-hydroxysteroid dehydrogenase. Chain: a. Synonym: type i 17beta-hydroxysteroid dehydrogenase. Ec: 1.1.1.62

Source:

Homo sapiens. Human. Organism_taxid: 9606

Biol. unit:

Dimer (from PQS)

Resolution:

2.20Å R-factor: 0.185 R-free: 0.229

Authors:

D.Ghosh

Key ref:

D.Ghosh et al. (1995). Structure of human estrogenic 17 beta-hydroxysteroid dehydrogenase at 2.20 A resolution. Structure, 3, 503-513. PubMed id: 7663947 DOI: 10.1016/S0969-2126(01)00183-6

Date:

19-Apr-95 Release date: 07-Dec-96

Protein chain

P14061  (DHB1_HUMAN) -  17-beta-hydroxysteroid dehydrogenase type 1 from Homo sapiens

Seq: 328 a.a.

Struc: 284 a.a.

Enzyme reactions

• Enzyme class 1: E.C.1.1.1.51 - 3(or 17)beta-hydroxysteroid dehydrogenase.
• Reaction:
  1. testosterone + NAD⁺ = androst-4-ene-3,17-dione + NADH + H⁺
  2. testosterone + NADP⁺ = androst-4-ene-3,17-dione + NADPH + H⁺
• Enzyme class 2: E.C.1.1.1.62 - 17beta-estradiol 17-dehydrogenase.
• Reaction:
  1. 17beta-estradiol + NAD⁺ = estrone + NADH + H⁺
  2. 17beta-estradiol + NADP⁺ = estrone + NADPH + H⁺

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1016/S0969-2126(01)00183-6

Structure 3:503-513 (1995)

PubMed id: 7663947

Structure of human estrogenic 17 beta-hydroxysteroid dehydrogenase at 2.20 A resolution.

D.Ghosh, V.Z.Pletnev, D.W.Zhu, Z.Wawrzak, W.L.Duax, W.Pangborn, F.Labrie, S.X.Lin.

ABSTRACT

BACKGROUND: The principal human estrogen, 17 beta-estradiol, is a potent stimulator of certain endocrine-dependent forms of breast cancer. Because human estrogenic 17 beta-hydroxysteroid dehydrogenase (type I 17 beta-HSD) catalyzes the last step in the biosynthesis of 17 beta-estradiol from the less potent estrogen, estrone, it is an attractive target for the design of inhibitors of estrogen production and tumor growth. This human enzyme shares less than 15% sequence identity with a bacterial 3 alpha,20 beta-HSD, for which the three-dimensional structure is known. The amino acid sequence of 17 beta-HSD also differs from that of bacterial 3 alpha,20 beta-HSD by two insertions (of 11 and 14 residues) and 52 additional residues at the C terminus. RESULTS: The 2.20 A resolution structure of type I 17 beta-HSD, the first mammalian steroidogenic enzyme studied by X-ray crystallographic techniques, reveals a fold characteristic of the short-chain dehydrogenases. The active site contains a Tyr-X-X-X-Lys sequence (where X is any amino acid) and a serine residue, features that are conserved in short-chain steroid dehydrogenases. The structure also contains three alpha-helices and a helix-turn-helix motif, not observed in short-chain dehydrogenase structures reported previously. No cofactor density could be located. CONCLUSIONS: The helices present in 17 beta-HSD that were not in the two previous short-chain dehydrogenase structures are located at one end of the substrate-binding cleft away from the catalytic triad. These helices restrict access to the active site and appear to influence substrate specificity. Modeling the position of estradiol in the active site suggests that a histidine side chain may play a critical role in substrate recognition. One or more of these helices may also be involved in the reported association of the enzyme with membranes. A model for steroid and cofactor binding as well as for the estrone to estradiol transition state is proposed. The structure of the active site provides a rational basis for designing more specific inhibitors of this breast cancer associated enzyme.

Selected figure(s)

Figure 1.
Figure 1. (a) Stereo ribbon diagram of a monomer of human estrogenic 17β-hydroxysteroid dehydrogenase (HSD). The course of the polypeptide chain is shown for residues 1–284. α-helices are drawn as magenta coils, β-strands as blue arrows, and turns and loops as green ropes. The side chains for residues in the active site belonging to the catalytic triad, Tyr155-Lys159-Ser142, are shown in white. The view is almost parallel to the central β-sheet. (Figure prepared using the program SETOR [43].) (b) Folding topology of strands (triangles) and helices (circles) in 17β-HSD. Figure 1. (a) Stereo ribbon diagram of a monomer of human estrogenic 17β-hydroxysteroid dehydrogenase (HSD). The course of the polypeptide chain is shown for residues 1–284. α-helices are drawn as magenta coils, β-strands as blue arrows, and turns and loops as green ropes. The side chains for residues in the active site belonging to the catalytic triad, Tyr155-Lys159-Ser142, are shown in white. The view is almost parallel to the central β-sheet. (Figure prepared using the program SETOR [[4]43].) (b) Folding topology of strands (triangles) and helices (circles) in 17β-HSD.

Figure 9.
Figure 9. Helices (a) αG′ and (b) αH viewed along the helical axis. The side chains are color coded to illustrate their amphiphilicity, as follows: green, hydrophobic; red, charged; and magenta, residues having a proton-donating functional group. Figure 9. Helices (a) αG′ and (b) αH viewed along the helical axis. The side chains are color coded to illustrate their amphiphilicity, as follows: green, hydrophobic; red, charged; and magenta, residues having a proton-donating functional group. (Figure prepared using the program SETOR [[3]43].)

The above figures are reprinted by permission from Cell Press: Structure (1995, 3, 503-513) copyright 1995.

Figures were selected by an automated process.