 |
PDBsum entry 1nq2
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Hormone/growth factor receptor
|
PDB id
|
|
|
|
1nq2
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Two resistance to thyroid hormone mutants with impaired hormone binding.
|
|
|
Authors
|
|
B.R.Huber,
B.Sandler,
B.L.West,
S.T.Cunha lima,
H.T.Nguyen,
J.W.Apriletti,
J.D.Baxter,
R.J.Fletterick.
|
|
|
Ref.
|
|
Mol Endocrinol, 2003,
17,
643-652.
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
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.
|
|
|
|
|
|
|
