1hj1

From Proteopedia

RAT OESTROGEN RECEPTOR BETA LIGAND-BINDING DOMAIN IN COMPLEX WITH PURE ANTIOESTROGEN ICI164,384

PDB ID 1hj1

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Structural highlights

1hj1 is a 1 chain structure with sequence from Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.3Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

ESR2_RAT Binds estrogens with an affinity similar to that of ER-alpha, and activates expression of reporter genes containing estrogen response elements (ERE) in an estrogen-dependent manner. Isoform 3 and isoform 4 are unable to bind DNA and activate transcription due to the truncation of the DNA binding domain. Isoform 2 shows loss of ligand binding affinity and suppresses ER-alpha and ER-beta1 mediated transcriptional activation and may act as a dominant negative regulator of estrogen action.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

BACKGROUND: Estrogens exert their effects on target tissues by binding to a nuclear transcription factor termed the estrogen receptor (ER). Previous structural studies have demonstrated that each class of ER ligand (agonist, partial agonist, and SERM antagonist) induces distinctive orientations in the receptor's carboxy-terminal transactivation helix. The conformation of this portion of the receptor determines whether ER can recruit and interact with the components of the transcriptional machinery, thereby facilitating target gene expression. RESULTS: We have determined the structure of rat ERbeta ligand binding domain (LBD) in complex with the pure antiestrogen ICI 164,384 at 2.3 A resolution. The binding of this compound to the receptor completely abolishes the association between the transactivation helix (H12) and the rest of the LBD. The structure reveals that the terminal portion of ICI's bulky side chain substituent protrudes from the hormone binding pocket, binds along the coactivator recruitment site, and physically prevents H12 from adopting either its characteristic agonist or AF2 antagonist orientation. CONCLUSIONS: The binding mode adopted by the pure antiestrogen is similar to that seen for other ER antagonists. However, the size and resultant positioning of the ligand's side chain substituent produces a receptor conformation that is distinct from that adopted in the presence of other classes of ER ligands. The novel observation that binding of ICI results in the complete destabilization of H12 provides some indications as to a possible mechanism for pure receptor antagonism.

Structural insights into the mode of action of a pure antiestrogen.,Pike AC, Brzozowski AM, Walton J, Hubbard RE, Thorsell AG, Li YL, Gustafsson JA, Carlquist M Structure. 2001 Feb 7;9(2):145-53. PMID:11250199^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Pike AC, Brzozowski AM, Walton J, Hubbard RE, Thorsell AG, Li YL, Gustafsson JA, Carlquist M. Structural insights into the mode of action of a pure antiestrogen. Structure. 2001 Feb 7;9(2):145-53. PMID:11250199