PDBsum entry 1dht

Oxidoreductase

PDB id: 1dht

Contents

Protein chain

284 a.a. *

Ligands

DHT

Waters ×52

* Residue conservation analysis

PDB id:

1dht

Name:

Oxidoreductase

Title:

Estrogenic 17-beta hydroxysteroid dehydrogenase complexed dihydrotestosterone

Structure:

Estrogenic 17-beta hydroxysteroid dehydrogenase. Chain: a. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Organ: placenta. Expressed in: escherichia coli. Expression_system_taxid: 562

Biol. unit:

Dimer (from PQS)

Resolution:

2.24Å R-factor: 0.188 R-free: 0.279

Authors:

Q.Han,R.L.Campbell,A.Gangloff,S.X.Lin

Key ref:

Q.Han et al. (2000). Dehydroepiandrosterone and dihydrotestosterone recognition by human estrogenic 17beta-hydroxysteroid dehydrogenase. C-18/c-19 steroid discrimination and enzyme-induced strain. J Biol Chem, 275, 1105-1111. PubMed id: 10625652 DOI: 10.1074/jbc.275.2.1105

Date:

25-Mar-98 Release date: 25-Sep-99

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⁺

testosterone + NAD(+) (Bound ligand (Het Group name = DHT) corresponds exactly) = androst-4-ene-3,17-dione + NADH + H(+)

testosterone + NADP(+) (Bound ligand (Het Group name = DHT) corresponds exactly) = 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⁺

17beta-estradiol + NAD(+) = estrone (Bound ligand (Het Group name = DHT) matches with 95.24% similarity) + NADH + H(+)

17beta-estradiol + NADP(+) = estrone (Bound ligand (Het Group name = DHT) matches with 95.24% similarity) + 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: 10.1074/jbc.275.2.1105

J Biol Chem 275:1105-1111 (2000)

PubMed id: 10625652

Dehydroepiandrosterone and dihydrotestosterone recognition by human estrogenic 17beta-hydroxysteroid dehydrogenase. C-18/c-19 steroid discrimination and enzyme-induced strain.

Q.Han, R.L.Campbell, A.Gangloff, Y.W.Huang, S.X.Lin.

ABSTRACT

Steroid hormones share a very similar structure, but they behave distinctly. We present structures of human estrogenic 17beta-hydroxysteroid dehydrogenase (17beta-HSD1) complexes with dehydroepiandrosterone (DHEA) and dihydrotestosterone (DHT), providing the first pictures to date of DHEA and DHT bound to a protein. Comparisons of these structures with that of the enzyme complexed with the most potent estrogen, estradiol, revealed the structural basis and general model for sex hormone recognition and discrimination. Although the binding cavity is almost entirely composed of hydrophobic residues that can make only nonspecific interactions, the arrangement of residues is highly complementary to that of the estrogenic substrate. Relatively small changes in the shape of the steroid hormone can significantly affect the binding affinity and specificity. The K(m) of estrone is more than 1000-fold lower than that of DHEA and the K(m) of estradiol is about 10 times lower than that of DHT. The structures suggest that Leu-149 is the primary contributor to the discrimination of C-19 steroids and estrogens by 17beta-HSD1. The critical role of Leu-149 has been well confirmed by site-directed mutagenesis experiments, as the Leu-149 --> Val variant showed a significantly decreased K(m) for C-19 steroids while losing discrimination between estrogens and C-19 steroids. The electron density of DHEA also revealed a distortion of its 17-ketone toward a beta-oriented form, which approaches the transition-state conformation for DHEA reduction.

Selected figure(s)

Figure 1.
Fig. 1. Chemical structures of cyclo-pentenophenanthrene ring, estrane ring, androstane ring, pregnane ring, DHEA, progesterone, estradiol, and DHT.

Figure 6.
Fig. 6. A side-by-side comparison of D-ring conformations. The normal model of DHEA (right) is the energy-minimized structure, which is very similar to the small molecule crystal structure of DHEA (21). The D-ring conformation of the model of 5-androstene-3,17-diol, the product of the reduction of DHEA (left), was made using Insight II by referring to the conformation of E[2]. The conformation of O-17 and the D-ring of DHEA changes from -oriented toward an -oriented position during the reduction reaction. The strained model of DHEA is also shown (center).

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2000, 275, 1105-1111) copyright 2000.

Figures were selected by an automated process.