1lhw
From Proteopedia
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'''CRYSTAL STRUCTURE OF THE N-TERMINAL LG-DOMAIN OF SHBG IN COMPLEX WITH 2-METHOXYESTRADIOL''' | '''CRYSTAL STRUCTURE OF THE N-TERMINAL LG-DOMAIN OF SHBG IN COMPLEX WITH 2-METHOXYESTRADIOL''' | ||
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[[Category: Muller, Y A.]] | [[Category: Muller, Y A.]] | ||
[[Category: 2-methoxyestradiol]] | [[Category: 2-methoxyestradiol]] | ||
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Revision as of 20:56, 2 May 2008
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. 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 Page seeded by OCA on Fri May 2 23:56:12 2008
