TY - JOUR
T1 - Ligand selectivity by seeking hydrophobicity in thyroid hormone receptor
AU - Borngraeber, Sabine
AU - Budny, Mary Jane
AU - Chiellini, Grazia
AU - Cunha-Lima, Suzana T.
AU - Togashi, Marie
AU - Webb, Paul
AU - Baxter, John D.
AU - Scanlan, Thomas S.
AU - Fletterick, Robert J.
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2003/12/23
Y1 - 2003/12/23
N2 - Selective therapeutics for nuclear receptors would revolutionize treatment for endocrine disease. Specific control of nuclear receptor activity is challenging because the internal cavities that bind hormones can be virtually identical. Only one highly selective hormone analog is known for the thyroid receptor, GC-24, an agonist for human thyroid hormone receptor β. The compound differs from natural hormone in benzyl, substituting for an iodine atom in the 3′ position. The benzyl is too large to fit into the enclosed pocket of the receptor. The crystal structure of human thyroid hormone receptor β at 2.8-Å resolution with GC-24 bound explains its agonist activity and unique isoform specificity. The benzyl of GC-24 is accommodated through shifts of 3-4 Å in two helices. These helices are required for binding hormone and positioning the critical helix 12 at the C terminus. Despite these changes, the complex associates with coactivator as tightly as human thyroid hormone receptor bound to thyroid hormone and is fully active. Our data suggest that increased specificity of ligand recognition derives from creating a new hydrophobic cluster with ligand and protein components.
AB - Selective therapeutics for nuclear receptors would revolutionize treatment for endocrine disease. Specific control of nuclear receptor activity is challenging because the internal cavities that bind hormones can be virtually identical. Only one highly selective hormone analog is known for the thyroid receptor, GC-24, an agonist for human thyroid hormone receptor β. The compound differs from natural hormone in benzyl, substituting for an iodine atom in the 3′ position. The benzyl is too large to fit into the enclosed pocket of the receptor. The crystal structure of human thyroid hormone receptor β at 2.8-Å resolution with GC-24 bound explains its agonist activity and unique isoform specificity. The benzyl of GC-24 is accommodated through shifts of 3-4 Å in two helices. These helices are required for binding hormone and positioning the critical helix 12 at the C terminus. Despite these changes, the complex associates with coactivator as tightly as human thyroid hormone receptor bound to thyroid hormone and is fully active. Our data suggest that increased specificity of ligand recognition derives from creating a new hydrophobic cluster with ligand and protein components.
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U2 - 10.1073/pnas.2136689100
DO - 10.1073/pnas.2136689100
M3 - Article
C2 - 14673100
AN - SCOPUS:0347364651
VL - 100
SP - 15358
EP - 15363
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 26
ER -