PDBsum entry 1nq2

Hormone/growth factor receptor

PDB id: 1nq2

Contents

Protein chain

255 a.a. *

Ligands

4HY

ARS ×5

Metals

_NA

Waters ×219

* Residue conservation analysis

PDB id:

1nq2

Name:

Hormone/growth factor receptor

Title:

Two rth mutants with impaired hormone binding

Structure:

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

2.40Å R-factor: 0.227 R-free: 0.264

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

Key ref:

B.R.Huber et al. (2003). Two resistance to thyroid hormone mutants with impaired hormone binding. Mol Endocrinol, 17, 643-652. PubMed id: 12554782

Date:

21-Jan-03 Release date: 15-Apr-03

Protein chain

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

Seq: 461 a.a.

Struc: 255 a.a.*

* PDB and UniProt seqs differ at 6 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.?

Mol Endocrinol 17:643-652 (2003)

PubMed id: 12554782

Two resistance to thyroid hormone mutants with impaired hormone binding.

B.R.Huber, B.Sandler, B.L.West, S.T.Cunha Lima, H.T.Nguyen, J.W.Apriletti, J.D.Baxter, R.J.Fletterick.

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.