Identification of a New Hormone-Binding Site on the Surface of Thyroid Hormone Receptor

Author(s)

Souza, P. C. T. ^[1] ; Puhl, A. C. ^[2] ; Martinez, L. ^[1] ; Aparicio, R. ^[1] ; Nascimento, A. S. ^[2] ; Figueira, A. C. M. ^[3] ; Nguyen, P. ^[4] ; Webb, P. ^{[2, 5]} ; Skaf, M. S. ^[1] ; Polikarpov, I. ^[2]

Affiliation

^[1] State Univ Campinas UNICAMP, Inst Chem, Campinas, SP - Brazil

^[2] Univ Sao Paulo, Inst Phys Sao Carlos, Sao Carlos, SP - Brazil

^[3] CNPEM, Natl Lab Biosci, Campinas, SP - Brazil

^[4] Univ Calif San Francisco, Med Ctr, Ctr Diabet, San Francisco, CA - USA

^[5] Houston Methodist Res Inst, Houston, TX - USA

• Document type: Journal article
• Source: MOLECULAR ENDOCRINOLOGY; v. 28, n. 4, p. 534-545, APR 2014.
• Web of Science Citations: 18

Abstract

Thyroid hormone receptors (TRs) are members of the nuclear receptor superfamily of ligand-activated transcription factors involved in cell differentiation, growth, and homeostasis. Although X-ray structures of many nuclear receptor ligand-binding domains (LBDs) reveal that the ligand binds within the hydrophobic core of the ligand-binding pocket, a few studies suggest the possibility of ligands binding to other sites. Here, we report a new x-ray crystallographic structure of TR-LBD that shows a second binding site for T-3 and T-4 located between H9, H10, and H11 of the TR alpha LBD surface. Statistical multiple sequence analysis, site-directed mutagenesis, and cell transactivation assays indicate that residues of the second binding site could be important for the TR function. We also conducted molecular dynamics simulations to investigate ligand mobility and ligand-protein interaction for T-3 and T-4 bound to this new TR surface-binding site. Extensive molecular dynamics simulations designed to compute ligand-protein dissociation constant indicate that the binding affinities to this surface site are of the order of the plasma and intracellular concentrations of the thyroid hormones, suggesting that ligands may bind to this new binding site under physiological conditions. Therefore, the second binding site could be useful as a new target site for drug design and could modulate selectively TR functions. (AU)

• FAPESP's process: 13/08293-7 - CCES - Center for Computational Engineering and Sciences
• Grantee: Munir Salomao Skaf
• Support type: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 10/17048-8 - Regulation of genic transactivation and transrepression mediated by nuclear receptors
• Grantee: Ana Carolina Migliorini Figueira
• Support type: Regular Research Grants