Oestrogen Receptors
The nuclear receptor family
ERs are part of a large, structurally conserved family of nuclear receptors. The nuclear receptor family includes receptors for ligands such as steroid hormones, vitamin D, retinoids and thyroid hormones, as well as putative orphan receptors for which no ligand has been identified. Several receptors are inducible with low-affinity ligands such as bile acids, long-chain fatty acids and xenobiotics. Several members of this superfamily have been implicated in various disease processes, including the androgen receptor in prostate cancer and the retinoic acid receptor alpha in acute promyelocytic leukaemia.
The closest members of the nuclear receptor family to the ERs are a group of receptors known as the oestrogen-related receptors (ERR). Three ERR orphan receptors have been identified: ERRa (helps control bone physiology; may act as a repressor of ER action in normal breast tissue), ERRb (essential for reproduction) and ERRg (regulates expression of the ER cofactor SHP). None of the ERRs bind oestrogen, but they are structurally close to the ERs, they can bind synthetic ER ligands, and they can activate transcription from ERE (oestrogen-response element)-containing reporter constructs. As such the ERRs share target genes with the ERs and can influence the oestrogenic response. ERRs are medically important, because ER antagonists do not necessarily bind to the ERRs, and as such may be free to activate ER-regulated genes.
P03372 Human oestrogen receptor ERa entry from InterPro
|
Interpro Entry |
Method accession |
Graphical match |
Method name
|
|
IPR000536 |
PF00104 |
|
hormone_rec |
|
IPR000536 |
SM00430 |
|
HOLI |
|
IPR001292 |
PF02159 |
|
OESTROGENR |
|
IPR001292 |
PR00543 |
|
Oest_recep |
|
IPR001628 |
PD000035 |
|
Znf_C4steroid |
|
IPR001628 |
PF00105 |
|
STROIDFINGER |
|
IPR001628 |
PR00047 |
|
zf-C4 |
|
IPR001628 |
PS00031 |
|
NUCLEAR_RECEPTOR |
|
IPR001628 |
SM00399 |
|
ZnF_C4 |
|
IPR001723 |
PR00398 |
|
STRDHORMONER |
|
IPR008946 |
SSF48508 |
|
SteroidR_ligand |
|
NONE |
1a52A0 |
|
|
|
NONE |
1hcqA0 |
|
|
|
NONE |
d1a52a_ |
|
|
|
NONE |
d1hcqa_ |
|
|
What InterPro tells us
From the graphical match above, you can see that the signatures in InterPro for ERa are subdivided into groups. These groups give you information about the domain architecture of the protein, as well as its family relationships.
Starting with the domain architecture of ERa, there are three major domains represented above: the N-terminal AF-1 domain, the DNA-binding domain (DBD) and the ligand-binding domain (LBD) (which contains the AF-2 site). The last four entries in the table above are from the structural classification databases CATH and SCOP (the names such as d1a52a are derived from the PDB entry that they are based on; here PDB entry 1a52 chain a). If you follow the links to these databases, you will find descriptions of the structural features and classification of these domains, as well as links to the corresponding PDB entries. There are also InterPro entries describing these domains. IPR000536 has two signatures representing the C-terminal LBD domain, as shown above. These signatures are PF00104 from the PFAM database and SM00430 from the SMART database, which were obtained from alignments of 191 and 308 nuclear receptor proteins, respectively, including ERa. The LBD is conserved in most nuclear receptors; as a result, this entry has a large number of protein representatives. Both CATH [1a52A0] and SCOP [d1a52a_ ] provide a structural classification of the ERa LBD and links to the PDB structures.
IPR001628 has five signatures
representing the two zinc finger motifs within the DBD, as shown above. These signatures are PD000035 from ProDom, PF00105
from PFAM, PR00047 from PRINTS, PS00031
from Prosite and SM00399 from SMART.
This InterPro entry has many protein representatives, because the DBD
zinc finger motifs are highly conserved in most nuclear receptors. CATH [1hcqA0] and SCOP [d1hcqa_] provide a structural classification of the ERa DBD
and links to the corresponding PDB structures.
The N-terminal AF-2 site of ERa is represented by the IPR001292 entry, which has two signatures. These signatures are PF02159 from PFAM and PR00543 from PRINTS. These signatures are unique to the AF-2 domain of ERa, and as such are have few protein representatives. There are no structural representatives of this domain.
The hinge domain between the DBD and the LBD is not well represented, because it tends to be a poorly conserved region with little secondary structure.
The IPR001723 entry represents the steroid hormone receptor and is represented by one signature, PR00398, from the PRINTS database. This signature was obtained from a five-element fingerprint derived from an initial alignment of 31 sequences; one of these motifs is within a DBD zinc finger, while the remaining four lies within the LBD. This family contains all the nuclear receptors that bind to steroid hormones, as well as their closest relatives. The IPR008946 entry represents the steroid nuclear receptor LBD and is represented by one signature, SSF48508, from the Superfamily database. The signature is based on an initial alignment of twelve sequences.
What
the structure tells us
A description and visualisation of the structural features of the oestrogen receptors can be found at the PDB database. Here you can see how different ligands can bind to the ER to bring about the conformational changes needed for its specific modes of action.
Other Databases
There are several nuclear receptor databases available that provide additional information. If you would like to find out more about the oestrogen receptor, there is the Estrogen Receptor Resource, which includes information on the domains, DNA binding elements, sequence and clinical data. This resource is part of the Nuclear Receptor Resource, which is a collection of individual databases on members of the nuclear receptor family. There is also the Nuclear Receptor Mutation Database, and the NucleaRDB, which provide information on all nuclear receptor family members.
Next: Table of the Nuclear Receptors