Linked Life Data

12554782

Source:http://linkedlifedata.com/resource/pubmed/id/12554782

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2003-3-28
pubmed:abstractText
Resistance to hormones is commonly due to mutations in genes encoding receptors. Resistance to thyroid hormone is due mostly to mutations of the beta-form of the human (h) thyroid hormone receptor (hTRbeta). We determined x-ray crystal structures of two hTRbeta 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 hTRbeta. Although 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 resistance to thyroid hormone 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. 3,5,3'-Triiodothyroacetic acid is bound to both receptors. Thr 317 repositions 3,5,3'-triiodothyroacetic acid 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 DNA-binding domain-LBD configuration.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
0888-8809
pubmed:author
pubmed:issnType
Print
pubmed:volume
17
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
643-52
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
2003
pubmed:articleTitle
Two resistance to thyroid hormone mutants with impaired hormone binding.
pubmed:affiliation
University of California, San Francisco, Department of Biochemistry Biophysics, 513 Parnassus Avenue, San Francisco, California 94143-0448, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.