PDBsum entry 1lhw

Transport protein

PDB id: 1lhw

Contents

Protein chain

174 a.a. *

Ligands

ESM

IPA

Metals

_CA

Waters ×97

* Residue conservation analysis

PDB id:

1lhw

Name:

Transport protein

Title:

Crystal structure of the n-terminal lg-domain of shbg in complex with 2-methoxyestradiol

Structure:

Sex hormone-binding globulin. Chain: a. Fragment: lg-like 1 domain, residues 30-218. 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:

1.75Å R-factor: 0.210 R-free: 0.238

Authors:

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

Key ref:

G.V.Avvakumov et al. (2002). Crystal structure of human sex hormone-binding globulin in complex with 2-methoxyestradiol reveals the molecular basis for high affinity interactions with C-2 derivatives of estradiol. J Biol Chem, 277, 45219-45225. PubMed id: 12228253 DOI: 10.1074/jbc.M207762200

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: 174 a.a.

DOI no: 10.1074/jbc.M207762200

J Biol Chem 277:45219-45225 (2002)

PubMed id: 12228253

Crystal structure of human sex hormone-binding globulin in complex with 2-methoxyestradiol reveals the molecular basis for high affinity interactions with C-2 derivatives of estradiol.

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

ABSTRACT

In a crystal structure of the amino-terminal laminin G-like domain of human sex hormone-binding globulin (SHBG), the biologically active estrogen metabolite, 2-methoxyestradiol (2-MeOE2), binds in the same orientation as estradiol. The high affinity of SHBG for 2-MeOE2 relies primarily on hydrogen bonding between the hydroxyl at C-3 of 2-MeOE2 and Asp(65) and an interaction between the methoxy group at C-2 and the amido group of Asn(82). Accommodation of the 2-MeOE2 methoxy group causes an outward displacement of residues Ser(128)-Pro(130), which appears to disorder and displace the loop region (Leu(131)-His(136)) that covers the steroid-binding site. This could influence the binding kinetics of 2-MeOE2 and/or facilitate ligand-dependent interactions between SHBG and other proteins. Occupancy of a zinc-binding site reduces the affinity of SHBG for 2-MeOE2 and estradiol in the same way. The higher affinity of SHBG for estradiol derivatives with a halogen atom at C-2 is due to either enhanced hydrogen bonding between the hydroxyl at C-3 and Asp(65) (2-fluoroestradiol) or accommodation of the functional group at C-2 (2-bromoestradiol), rather than an interaction with Asn(82). By contrast, the low affinity of SHBG for 2-hydroxyestradiol can be attributed to intra-molecular hydrogen bonding between the hydroxyls in the aromatic steroid ring A, which generates a steric clash with the amido group of Asn(82). Understanding how C-2 derivatives of estradiol interact with SHBG could facilitate the design of biologically active synthetic estrogens.

Selected figure(s)

Figure 1.
Fig. 1. Stereo representation of the human SHBG in complex with 2-MeOe2. A, details of the interaction between SHBG and 2-MeOE2 (in orange). The dashed lines indicate possible hydrogen bonds between functional groups at C-2, C-3, and C-17 of 2-MeOE2 and the corresponding amino acid side chains. The numbering of carbon atoms in the steroid molecule follows the IUPAC-IUB guidelines; the methoxy group at C-2 can hydrogen-bond to Asn82; the hydroxyl at C-3 can hydrogen-bond to Asp65 and Asn82, and the hydroxyl at C-17 can hydrogen-bond to Ser42 and the carbonyl oxygen of Val105. B, the conformation of the loop segment that covers the steroid-binding site in the 2-MeOE2 complex (in orange) differs from that observed in SHBG in complex with estradiol (in red, accession code 1LHU) and DHT (in blue, accession code 1KDK). No electron density is observed for residues Leu131, Thr132, and Ser133 in the 2-MeOE2 complex. The figures were generated using Molscript (30) and Raster3d (31).

Figure 5.
Fig. 5. Model to explain how intramolecular hydrogen bonding in 2-hydroxyestradiol impacts negatively on its interaction with Asn82 within the human SHBG steroid-binding site. Ring A of 2-hydroxyestradiol and the carbamide group of Asn82, with attached hydrogen atoms (black dots), are modeled using the coordinates of the crystal structures of catechol (24) and asparagine monohydrate (32), respectively. When assuming that the hydroxyl at C-3 of 2-hydroxyestradiol forms a hydrogen bond with the carboxylate group of Asp65, a steric clash will occur between the hydroxyl at C-2 of the steroid ring A and the amido group of Asn82.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2002, 277, 45219-45225) copyright 2002.

Figures were selected by an automated process.