1LHW

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

Summary for 1LHW

• Entry DOI: 10.2210/pdb1lhw/pdb
• Related: 1D2S 1F5F 1KDK 1KDM 1LHN 1LHO 1LHU 1LHV
• Descriptor: SEX HORMONE-BINDING GLOBULIN, CALCIUM ION, 1,3,5(10)-ESTRATRIEN-2,3,17-BETA-TRIOL 2-METHYL ETHER, ... (5 entities in total)
• Functional Keywords: shbg, 2-methoxyestradiol, transport protein
• Biological source: Homo sapiens (human)
• Cellular location: Secreted : P04278
• Total number of polymer chains: 1
• Total formula weight: 21375.41

Authors

Avvakumov, G.V.,Grishkovskaya, I.,Muller, Y.A.,Hammond, G.L. (deposition date: 2002-04-17, release date: 2002-10-23, Last modification date: 2024-11-20)

Primary citation

Avvakumov, G.V.,Grishkovskaya, I.,Muller, Y.A.,Hammond, G.L.
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, 2002

PubMed 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.

PubMed: 12228253
DOI: 10.1074/jbc.M207762200

Experimental method

X-RAY DIFFRACTION (1.75 Å)