2xn3
Crystal structure of thyroxine-binding globulin complexed with mefenamic acid
Structural highlights
DiseaseTHBG_HUMAN Defects in SERPINA7 are a cause of thyroxine-binding globulin deficiency (TBG deficiency) [MIM:314200. Mutations in the SERPINA7 gene can result as a whole spectrum of deficiencies, characterized by either reduced or increased TBG levels in the serum. Patients show, respectively, reduced or elevated protein-bound iodine but are euthyroid. FunctionTHBG_HUMAN Major thyroid hormone transport protein in serum. Publication Abstract from PubMedThe release of hormones from thyroxine-binding globulin (TBG) and corticosteroid-binding globulin (CBG) is regulated by movement of the reactive-center loop in-and-out of the beta-sheet A of the molecule. To investigate how these changes are transmitted to the hormone-binding site we developed a sensitive assay using a synthesized thyroxine-fluorophore and solved the crystal structures of reactive-loop cleaved TBG together with its complexes with thyroxine, the thyroxine-fluorophores, furosemide, and mefenamic acid. Cleavage of the reactive-loop results in its complete insertion into the beta-sheet A and a substantial but incomplete decrease in binding affinity in both TBG and CBG. We show here that the direct interaction between residue P14 of the reactive loop and Tyr241 of the hormone binding site contributes to thyroxine binding and release following reactive loop insertion. However a much larger effect occurs allosterically due to stretching of the connecting-loop to the top of the D helix (hD) as confirmed in TBG with shortening of the loop by 3-residues making it insensitive to the S-to-R transition. The transmission of the changes in the hD-loop to the binding pocket is seen to involve coherent movements in the s2/3B loop linked to the hD-loop by Lys243 which is in turn linked to the s4/5B loop, flanking the thyroxine binding site, by Arg378. Overall the coordinated movements of the reactive-loop, hD and the hormone binding site, allow the allosteric regulation of hormone-release, as with the modulation demonstrated here in response to changes in temperature. Allosteric modulation of hormone release from thyroxine and corticosteroid binding-globulins.,Qi X, Loiseau F, Chan WL, Yan Y, Wei Z, Milroy LG, Myers RM, Ley SV, Read RJ, Carrell RW, Zhou A J Biol Chem. 2011 Feb 16. PMID:21325280[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
| ||||||||||||||||||||
