2XN6

Crystal structure of thyroxine-binding globulin complexed with thyroxine-fluoresein

Summary for 2XN6

• Entry DOI: 10.2210/pdb2xn6/pdb
• Related: 2CEO 2RIV 2RIW 2XN3 2XN5 2XN7
• Descriptor: THYROXINE-BINDING GLOBULIN, CALCIUM ION, 1,2-ETHANEDIOL, ... (7 entities in total)
• Functional Keywords: transport, cleaved protein
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Secreted: P05543 P05543
• Total number of polymer chains: 2
• Total formula weight: 45026.87

Authors

Qi, X.,Yan, Y.,Wei, Z.,Zhou, A. (deposition date: 2010-07-30, release date: 2011-02-16, Last modification date: 2023-12-20)

Primary citation

Qi, X.,Loiseau, F.,Chan, W.L.,Yan, Y.,Wei, Z.,Milroy, L.G.,Myers, R.M.,Ley, S.V.,Read, R.J.,Carrell, R.W.,Zhou, A.
Allosteric Modulation of Hormone Release from Thyroxine and Corticosteroid Binding-Globulins.
J.Biol.Chem., 286:16163-, 2011

PubMed Abstract: The 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 β-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 β-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 Thr(342) of the reactive loop and Tyr(241) 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 three 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 Lys(243), which is, in turn, linked to the s4/5B loop, flanking the thyroxine-binding site, by Arg(378). 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.

PubMed: 21325280
DOI: 10.1074/JBC.M110.171082

Experimental method

X-RAY DIFFRACTION (1.29 Å)