1Y0X

Thyroxine-Thyroid Hormone Receptor Interactions

Summary for 1Y0X

• Entry DOI: 10.2210/pdb1y0x/pdb
• Related: 1XZX
• Descriptor: Thyroid hormone receptor beta-1, CACODYLATE ION, 3,5,3',5'-TETRAIODO-L-THYRONINE, ... (4 entities in total)
• Functional Keywords: hormone/growth factor receptor, hormone-growth factor receptor complex
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: P10828
• Total number of polymer chains: 1
• Total formula weight: 33312.35

Authors

Sandler, B.,Webb, P.,Apriletti, J.W.,Huber, B.R.,Togashi, M.,Cunha Lima, S.T.,Juric, S.,Nilsson, S.,Wagner, R.,Fletterick, R.J.,Baxter, J.D. (deposition date: 2004-11-16, release date: 2004-12-07, Last modification date: 2024-04-03)

Primary citation

Sandler, B.,Webb, P.,Apriletti, J.W.,Huber, B.R.,Togashi, M.,Cunha Lima, S.T.,Juric, S.,Nilsson, S.,Wagner, R.,Fletterick, R.J.,Baxter, J.D.
Thyroxine-thyroid hormone receptor interactions.
J.Biol.Chem., 279:55801-55808, 2004

PubMed Abstract: Thyroid hormone (TH) actions are mediated by nuclear receptors (TRs alpha and beta) that bind triiodothyronine (T(3), 3,5,3'-triiodo-l-thyronine) with high affinity, and its precursor thyroxine (T(4), 3,5,3',5'-tetraiodo-l-thyronine) with lower affinity. T(4) contains a bulky 5' iodine group absent from T(3). Because T(3) is buried in the core of the ligand binding domain (LBD), we have predicted that TH analogues with 5' substituents should fit poorly into the ligand binding pocket and perhaps behave as antagonists. We therefore examined how T(4) affects TR activity and conformation. We obtained several lines of evidence (ligand dissociation kinetics, migration on hydrophobic interaction columns, and non-denaturing gels) that TR-T(4) complexes adopt a conformation that differs from TR-T(3) complexes in solution. Nonetheless, T(4) behaves as an agonist in vitro (in effects on coregulator and DNA binding) and in cells, when conversion to T(3) does not contribute to agonist activity. We determined x-ray crystal structures of the TRbeta LBD in complex with T(3) and T(4) at 2.5-A and 3.1-A resolution. Comparison of the structures reveals that TRbeta accommodates T(4) through subtle alterations in the loop connecting helices 11 and 12 and amino acid side chains in the pocket, which, together, enlarge a niche that permits helix 12 to pack over the 5' iodine and complete the coactivator binding surface. While T(3) is the major active TH, our results suggest that T(4) could activate nuclear TRs at appropriate concentrations. The ability of TR to adapt to the 5' extension should be considered in TR ligand design.

PubMed: 15466465
DOI: 10.1074/jbc.M410124200

Experimental method

X-RAY DIFFRACTION (3.1 Å)