help button home button Endocrine Society Molecular Endocrinology ENDO 08 Sessions Library
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
This version published online on January 16, 2003
Molecular Endocrinology, doi:10.1210/me.2002-0095
Molecular Endocrinology Vol. 0, No. 2003 200200951-
doi:10.1210/me.2002-0095
Copyright © 2003 by the Endocrine Society.
This Article
Right arrow Author Manuscript (PDF)
Right arrow All Versions of this Article:
17/4/643    most recent
Author Manuscript (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow NURSA Molecule Pages Link
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Huber, B. R.
Right arrow Articles by Fletterick, R. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Huber, B. R.
Right arrow Articles by Fletterick, R. J.
Right arrowPubmed/NCBI databases
*Gene*GEO Profiles
*HomoloGene*Protein
*Structure*UniGene
*Compound via MeSH
*Substance via MeSH
Hazardous Substances DB
*(L)-ARGININE
*(L)-HISTIDINE
*LIOTHYRONINE

Submitted on March 12, 2002
Accepted on January 2, 2003

Two RTH Mutants with Impaired Hormone Binding

B. Russell Huber1, Ben Sandler1, Brian L. West1, Suzana T. Cunha Lima1, Hoa T. Nguyen1, James W. Apriletti1, John D. Baxter1, and Robert J. Fletterick1*

1 Graduate Group in Biophysics (B.R.H.); Department of Biochemistry and Biophysics (B.S.,R.J.F.); Diabetes Center and the Metabolic Research Unit, Department of Medicine (B.L.W., S.T.C.L., H.T.N., J.W.A., J.D.B.); University of California, San Francisco, San Francisco, California 94143-0448

* To whom correspondence should be addressed. E-mail: flett{at}msg.ucsf.edu.

Resistance to hormones is commonly due to mutations in genes encoding receptors. Resistance to thyroid hormone (RTH) is due mostly to mutations of the {beta}-form of the human (h) thyroid hormone receptor (hTR{beta}). We determined X-ray crystal structures of two hTR{beta} ligand-binding domains (LBDs), Ala 317 Thr and Arg 316 His. Amino acids 316 and 317 form part of the hormone-binding pocket. The methyl of Ala 317, contacting iodine, sculpts the T3 hormone-binding pocket. Arg 316 is not in direct contact with T3, and has an unknown role in function. Remarkably, the Arg forms part of an unusual buried polar cluster in hTR{beta}. Though the identity of the amino acids changes, the polar cluster appears in all nuclear receptors. In spite of the differing roles of 316 and 317, both RTH mutants display decreased T3 affinity and weakened transcriptional activation. The two mutants differ in that the Arg 316 His receptor does not form TR-TR homodimers on DNA.

Triac (3, 5, 3'-triiodothyroacetic acid) is bound to both receptors. Thr 317 repositions Triac distending the face of the receptor that binds coregulators. Arg 316 forms two hydrogen bonds with helix 1. Both are lost with mutation to His displacing helix 1 of the LBD and disordering the loop after helix 1. The stability of the helix 1, deriving in part from the buried polar cluster, is important for hormone binding and formation of TR dimers. The observation that the Arg 316 His mutation affects these functions implies a role for helix 1 in linking hormone binding to the DBD-LBD configuration.
Key words: Thyroid disease • thyroid receptor • human mutations • X-ray crystallography • RTH

NURSA Molecule Pages Link:

Nuclear Receptors:   TRβ  |  RARα  |  PPARγ  |  VDR  |  PXR  |  RXRα  |  usp  |  ERα  |  PR  |  AR
Coregulators:   GRIP1
Ligands:   Thyroid hormone



This article has been cited by other articles:


Home page
 Biophys. JHome page
L. Martinez, M. T. Sonoda, P. Webb, J. D. Baxter, M. S. Skaf, and I. Polikarpov
Molecular Dynamics Simulations Reveal Multiple Pathways of Ligand Dissociation from Thyroid Hormone Receptors
Biophys. J., September 1, 2005; 89(3): 2011 - 2023.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
M. Togashi, P. Nguyen, R. Fletterick, J. D. Baxter, and P. Webb
Rearrangements in Thyroid Hormone Receptor Charge Clusters That Stabilize Bound 3,5',5-Triiodo-L-thyronine and Inhibit Homodimer Formation
J. Biol. Chem., July 8, 2005; 280(27): 25665 - 25673.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
W. Wan, B. Farboud, and M. L. Privalsky
Pituitary Resistance to Thyroid Hormone Syndrome Is Associated with T3 Receptor Mutants that Selectively Impair {beta}2 Isoform Function
Mol. Endocrinol., June 1, 2005; 19(6): 1529 - 1542.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
S. Borngraeber, M.-J. Budny, G. Chiellini, S. T. Cunha-Lima, M. Togashi, P. Webb, J. D. Baxter, T. S. Scanlan, and R. J. Fletterick
Ligand selectivity by seeking hydrophobicity in thyroid hormone receptor
PNAS, December 23, 2003; 100(26): 15358 - 15363.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals
Copyright © 2003 by The Endocrine Society