title: Gaining ligand selectivity in thyroid hormone receptors via entropy.
abstract: Nuclear receptors are important targets for pharmaceuticals, but similarities between family members cause difficulties in obtaining highly selective compounds. Synthetic ligands that are selective for thyroid hormone (TH) receptor beta (TRbeta) vs. TRalpha reduce cholesterol and fat without effects on heart rate; thus, it is important to understand TRbeta-selective binding. Binding of 3 selective ligands (GC-1, KB141, and GC-24) is characterized at the atomic level; preferential binding depends on a nonconserved residue (Asn-331beta) in the TRbeta ligand-binding cavity (LBC), and GC-24 gains extra selectivity from insertion of a bulky side group into an extension of the LBC that only opens up with this ligand. Here we report that the natural TH 3,5,3'-triodothyroacetic acid (Triac) exhibits a previously unrecognized mechanism of TRbeta selectivity. TR x-ray structures reveal better fit of ligand with the TRalpha LBC. The TRbeta LBC, however, expands relative to TRalpha in the presence of Triac (549 A(3) vs. 461 A(3)), and molecular dynamics simulations reveal that water occupies the extra space. Increased solvation compensates for weaker interactions of ligand with TRbeta and permits greater flexibility of the Triac carboxylate group in TRbeta than in TRalpha. We propose that this effect results in lower entropic restraint and decreases free energy of interactions between Triac and TRbeta, explaining subtype-selective binding. Similar effects could potentially be exploited in nuclear receptor drug design.
authors.affiliation: Instituto de Química, Universidade Estadual de Campinas, SP 13084-862, Campinas, Brazil.
authors.forename: Leandro
authors.initials: L
authors.lastname: Martínez
authors.forename: Alessandro S
authors.initials: AS
authors.lastname: Nascimento
authors.forename: Fabio M
authors.initials: FM
authors.lastname: Nunes
authors.forename: Kevin
authors.initials: K
authors.lastname: Phillips
authors.forename: Ricardo
authors.initials: R
authors.lastname: Aparicio
authors.forename: Sandra Martha G
authors.initials: SM
authors.lastname: Dias
authors.forename: Ana Carolina M
authors.initials: AC
authors.lastname: Figueira
authors.forename: Jean H
authors.initials: JH
authors.lastname: Lin
authors.forename: Phuong
authors.initials: P
authors.lastname: Nguyen
authors.forename: James W
authors.initials: JW
authors.lastname: Apriletti
authors.forename: Francisco A R
authors.initials: FA
authors.lastname: Neves
authors.forename: John D
authors.initials: JD
authors.lastname: Baxter
authors.forename: Paul
authors.initials: P
authors.lastname: Webb
authors.forename: Munir S
authors.initials: MS
authors.lastname: Skaf
authors.forename: Igor
authors.initials: I
authors.lastname: Polikarpov
mesh_terms: D019342:Acetic Acid / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D019277:Entropy; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D056004:Molecular Dynamics Simulation; D018583:Pliability; D055672:Static Electricity; D013816:Thermodynamics; D037021:Thyroid Hormone Receptors alpha / Q000378:metabolism*; D037042:Thyroid Hormone Receptors beta / Q000378:metabolism*; D014284:Triiodothyronine / Q000737:chemistry / Q000378:metabolism; D014867:Water
chemical_list: D008024:Ligands; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; D014867:Water; D014284:Triiodothyronine; D019342:Acetic Acid