1lhw

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spinqualitylabelsall models 1lhw, resolution 1.75Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

CRYSTAL STRUCTURE OF THE N-TERMINAL LG-DOMAIN OF SHBG IN COMPLEX WITH 2-METHOXYESTRADIOL

Overview

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.

About this Structure

1LHW is a Single protein structure of sequence from Homo sapiens with CA, ESM and IPA as ligands. Full crystallographic information is available from OCA.

Reference

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., Avvakumov GV, Grishkovskaya I, Muller YA, Hammond GL, J Biol Chem. 2002 Nov 22;277(47):45219-25. Epub 2002 Sep 11. PMID:12228253

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