PDBsum entry 1lhu

Transport protein

PDB id: 1lhu

Contents

Protein chain

175 a.a. *

Ligands

EST

Metals

_CA

Waters ×96

* Residue conservation analysis

PDB id:

1lhu

Name:

Transport protein

Title:

Crystal structure of the n-terminal lg-domain of shbg in complex with estradiol

Structure:

Sex hormone-binding globulin. Chain: a. Fragment: lg-like 1 domain, residues 43-218. Synonym: shbg, sex steroid-binding protein, sbp, testis-specific androgen-binding protein, abp. Engineered: yes

Source:

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

Biol. unit:

Hexamer (from PDB file)

Resolution:

1.80Å R-factor: 0.204 R-free: 0.237

Authors:

I.Grishkovskaya,G.V.Avvakumov,G.L.Hammond,M.G.Catalano,Y.A.Muller

Key ref:

I.Grishkovskaya et al. (2002). Steroid ligands bind human sex hormone-binding globulin in specific orientations and produce distinct changes in protein conformation. J Biol Chem, 277, 32086-32093. PubMed id: 12065592 DOI: 10.1074/jbc.M203999200

Date:

17-Apr-02 Release date: 23-Oct-02

Protein chain

P04278  (SHBG_HUMAN) -  Sex hormone-binding globulin from Homo sapiens

Seq: 402 a.a.

Struc: 175 a.a.

DOI no: 10.1074/jbc.M203999200

J Biol Chem 277:32086-32093 (2002)

PubMed id: 12065592

Steroid ligands bind human sex hormone-binding globulin in specific orientations and produce distinct changes in protein conformation.

I.Grishkovskaya, G.V.Avvakumov, G.L.Hammond, M.G.Catalano, Y.A.Muller.

ABSTRACT

The amino-terminal laminin G-like domain of human sex hormone-binding globulin (SHBG) contains a single high affinity steroid-binding site. Crystal structures of this domain in complex with several different steroid ligands have revealed that estradiol occupies the SHBG steroid-binding site in an opposite orientation when compared with 5 alpha-dihydrotestosterone or C19 androgen metabolites (5 alpha-androstan-3 beta,17 beta-diol and 5 alpha-androstan-3 beta,17 alpha-diol) or the synthetic progestin levonorgestrel. Substitution of specific residues within the SHBG steroid-binding site confirmed that Ser(42) plays a key role in determining high affinity interactions by hydrogen bonding to functional groups at C3 of the androstanediols and levonorgestrel and the hydroxyl at C17 of estradiol. Among residues participating in the hydrogen bond network with hydroxy groups at C17 of C19 steroids or C3 of estradiol, Asp(65) appears to be the most important. The different binding mode of estradiol is associated with a difference in the position/orientation of residues (Leu(131) and Lys(134)) in the loop segment (Leu(131)-His(136)) that covers the steroid-binding site as well as others (Leu(171)-Lys(173) and Trp(84)) on the surface of human SHBG and may provide a basis for ligand-dependent interactions between SHBG and other macromolecules. These new crystal structures have also enabled us to construct a simple space-filling model that can be used to predict the characteristics of novel SHBG ligands.

Selected figure(s)

Figure 2.
Fig. 2. Stereo images of the human SHBG steroid-binding site occupied by 3 ,17 Adiol (A), 3 ,17 Adiol (B), and levonorgestrel (C). The orientation of these ligands within the human SHBG steroid-binding site is similar to that observed previously for DHT (8). Images were prepared with Molscript (34) and Raster3d (35).

Figure 3.
Fig. 3. Estradiol binds to human SHBG in an opposite orientation when compared with 3 ,17 Adiol. A, stereo image of the human SHBG steroid-binding site occupied by estradiol. B, superposition of the steroid-binding site in the 3 ,17 Adiol (in blue) and estradiol (in yellow) complexes, illustrating the differences in steroid orientation and coordination. Images were prepared with Molscript (34) and Raster3d (35).

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2002, 277, 32086-32093) copyright 2002.

Figures were selected by an automated process.