PDBsum entry 1nq1

Hormone/growth factor receptor

PDB id

1nq1

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Contents

			Protein chain

					253 a.a. *

			Ligands

					4HY


					ARS ×2

* Residue conservation analysis

PDB id:

1nq1

Links

Name:

Hormone/growth factor receptor

Title:

Tr receptor mutations conferring hormone resistance and reduced corepressor release exhibit decreased stability in the nterminal lbd

Structure:

Thyroid hormone receptor beta-1. Chain: a. Fragment: ligand binding domain. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: thrb or nr1a2 or erba2 or thr1. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.90Å

R-factor:

0.239

R-free:

0.287

Authors:

B.R.Huber,M.Desclozeaux,B.L.West,S.T.Cunha-Lima,H.T.Nguyen, J.D.Baxter,H.A.Ingraham,R.J.Fletterick

Key ref:

B.R.Huber et al. (2003). Thyroid hormone receptor-beta mutations conferring hormone resistance and reduced corepressor release exhibit decreased stability in the N-terminal ligand-binding domain. Mol Endocrinol, 17, 107-116. PubMed id: 12511610

Date:

20-Jan-03

Release date:

15-Apr-03

PROCHECK

	Headers

	References

Protein chain

P10828 (THB_HUMAN) - Thyroid hormone receptor beta from Homo sapiens

Seq: Struc:					461 a.a. 253 a.a.*

Key:

PfamA domain

Secondary structure

CATH domain

* PDB and UniProt seqs differ at 5 residue positions (black crosses)



		Enzyme reactions

Enzyme class:

E.C.?

[IntEnz] [ExPASy] [KEGG] [BRENDA]

	Mol Endocrinol 17:107-116 (2003)
PubMed id: 12511610

Thyroid hormone receptor-beta mutations conferring hormone resistance and reduced corepressor release exhibit decreased stability in the N-terminal ligand-binding domain.
B.R.Huber, M.Desclozeaux, B.L.West, S.T.Cunha-Lima, H.T.Nguyen, J.D.Baxter, H.A.Ingraham, R.J.Fletterick.

ABSTRACT

Resistance to thyroid hormone (RTH) syndrome is associated with mutations in the human thyroid hormone receptor-beta (hTRbeta), many of which show marked reduction in hormone binding. Here, we investigated the structural consequences of two RTH mutants (A234T and R243Q), residing in the flexible N-terminal portion of the ligand binding domain (LBD), which exhibit modestly reduced hormone binding with impaired release of corepressor. X-ray crystallography analyses revealed that these two RTH mutants modulate the position of this flexible region by either altering the movement of helix 1 (A234T) or disrupting a salt bridge (R243Q). The subsequent increased flexibility and mobility in regions after the two sites of mutation coincided with a disorganized LBD. Consistent with this finding, the ability of these mutant N-terminal regions (234-260) to recruit the remaining LBD was decreased in a ligand-dependent helix assembly assay. Collectively, these data suggest that structural information imparted by the flexible segment in the N-terminal LBD is critical for overall stability of the LBD. Thus, these structural analyses provide mechanistic insight into the etiology of RTH disease in human TRbeta mutants that exhibit hormone binding with decreased ligand-dependent corepressor release.

Literature references that cite this PDB file's key reference

PubMed id

Reference

18836710

M.Peräkylä (2009).
Ligand unbinding pathways from the vitamin D receptor studied by molecular dynamics simulations.

Eur Biophys J, 38, 185-198.

19729063

S.T.Cunha Lima, N.H.Nguyen, M.Togashi, J.W.Apriletti, P.Nguyen, I.Polikarpov, T.S.Scanlan, J.D.Baxter, and P.Webb (2009).
Differential effects of TR ligands on hormone dissociation rates: evidence for multiple ligand entry/exit pathways.

J Steroid Biochem Mol Biol, 117, 125-131.

17218414

C.B.Harvey, J.H.Bassett, P.Maruvada, P.M.Yen, and G.R.Williams (2007).
The rat thyroid hormone receptor (TR) Deltabeta3 displays cell-, TR isoform-, and thyroid hormone response element-specific actions.

Endocrinology, 148, 1764-1773.

15980170

L.Martínez, M.T.Sonoda, P.Webb, J.D.Baxter, M.S.Skaf, and I.Polikarpov (2005).
Molecular dynamics simulations reveal multiple pathways of ligand dissociation from thyroid hormone receptors.

Biophys J, 89, 2011-2023.

15632172

M.L.Goodson, B.A.Jonas, and M.L.Privalsky (2005).
Alternative mRNA splicing of SMRT creates functional diversity by generating corepressor isoforms with different affinities for different nuclear receptors.

J Biol Chem, 280, 7493-7503.

15860414

S.Y.Cheng (2005).
Thyroid hormone receptor mutations and disease: beyond thyroid hormone resistance.

Trends Endocrinol Metab, 16, 176-182.

12820970

E.P.Sablin, I.N.Krylova, R.J.Fletterick, and H.A.Ingraham (2003).
Structural basis for ligand-independent activation of the orphan nuclear receptor LRH-1.

Mol Cell, 11, 1575-1585.

PDB code:

1pk5

14673100

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 (2003).
Ligand selectivity by seeking hydrophobicity in thyroid hormone receptor.

Proc Natl Acad Sci U S A, 100, 15358-15363.

PDB code:

1q4x

The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.