ESR1 Gene Complete Identifier and Functional Mapping Reference
Provide a comprehensive cross-database identifier and functional mapping reference for human ESR1 — a definitive lookup resource covering: ### Section 1: Gene identifiers For human gene ESR1, list ALL gene-level database identifiers. Required: - HGNC ID and approved symbol - Ensembl gene ID (ENSG...) - NCBI Entrez Gene ID - OMIM gene/locus ID - Genomic location: chromosome, start position, end position, strand (GRCh38) ### Section 2: Transcript identifiers For human gene ESR1, list ALL transcript-level identifiers. Required: - Ensembl transcripts: ALL ENST IDs with biotype. Total count. - RefSeq transcripts: ALL NM_ mRNA accessions. Mark which is MANE Select. - CCDS IDs. - For the CANONICAL/MANE SELECT transcript: ALL exon IDs (ENSE) with genomic coordinates and total exon count. ### Section 3: Protein identifiers For human gene ESR1 protein product(s), list ALL protein-level identifiers. Required: - UniProt accessions: ALL entries (reviewed and unreviewed). Mark the canonical reviewed entry. - RefSeq protein: ALL NP_ accessions. - Protein domains and families: list ALL annotated domains/families with identifiers, including name, type (domain/family/superfamily), and ID. - Antibody availability: known antibody resources for the protein. ### Section 4: Structure For human gene ESR1 protein, list ALL structural data. Required: - Experimental structures: ALL PDB IDs. For each: experimental method (X-ray/NMR/Cryo-EM) and resolution. Total count. - Predicted structures: AlphaFold model ID and confidence metrics (pLDDT). ### Section 5: Cross-species orthologs For human gene ESR1, list orthologous genes in key model organisms. Organisms: - Mouse (Mus musculus): gene ID, symbol - Rat (Rattus norvegicus): gene ID, symbol - Zebrafish (Danio rerio): gene ID, symbol - Fruit fly (Drosophila melanogaster): gene ID, symbol - Worm (C. elegans): gene ID, symbol - Yeast (S. cerevisiae): gene ID, symbol ### Section 6: Clinical variants & AI predictions For human gene ESR1, summarize clinical variants and AI predictions. Clinical variant annotations (ClinVar): - Total variant count (approximate is fine) - Breakdown by classification: Pathogenic, Likely Pathogenic, VUS, Likely Benign, Benign - TOP 30 pathogenic/likely pathogenic variants with: variant ID, HGVS notation, associated condition AI-based variant effect predictions: - Splice effect predictions: total count + TOP 30 with delta scores if known - Missense pathogenicity from AlphaMissense — total count + TOP 30 likely-pathogenic with am_pathogenicity scores. ### Section 7: Pathways & Gene Ontology For human gene ESR1, list biological pathways and Gene Ontology annotations. Pathway membership: - ALL biological pathways this gene participates in, with pathway IDs and names - Total pathway count Gene Ontology: - Biological Process: count and TOP 20 terms with GO IDs - Molecular Function: count and TOP 20 terms with GO IDs - Cellular Component: count and TOP 20 terms with GO IDs ### Section 8: Protein interactions & networks For human gene ESR1 protein, summarize protein interactions and networks. Protein-protein interactions (STRING, IntAct, BioGRID, etc.): - Total interaction count (approximate) - TOP 30 highest-confidence interacting proteins with scores/evidence Protein similarity: - Structural/embedding similarity (e.g. Foldseek, ESM): TOP 20 similar proteins with scores - Sequence homology: TOP 20 homologous proteins with identity/similarity ### Section 9: Transcription factor regulatory data For human gene ESR1, summarize transcription factor regulatory data. If ESR1 is a transcription factor: - Downstream targets: total count + TOP 30 with regulation type (activates/represses) and evidence - DNA binding motifs from JASPAR — all known motif IDs and motif family classification. Regardless: - Upstream regulators: TFs that regulate ESR1 — names with evidence type (ChIP-seq / predicted / experimentally validated) If ESR1 is not a transcription factor, say so briefly and skip the downstream/motif sections. ### Section 10: Drug & pharmacology data For human gene ESR1 protein as a drug target, summarize pharmacology data. If ESR1 is a known drug target: - Targeting molecules: total count in ChEMBL/DrugBank + TOP 30 by development phase (molecule ID, name, mechanism, highest phase) - Clinical trials: TOP 20 involving drugs targeting this gene — trial ID, phase, status, intervention - Pharmacogenomics: known drug-gene interactions affecting drug response + dosing guidelines if any If ESR1 is not currently a drug target, say so briefly. ### Section 11: Expression profiles For human gene ESR1, summarize expression profiles. Tissue expression (GTEx, HPA, Bgee, etc.): - TOP 30 tissues with expression scores/levels (direction, units if known) - Note tissue-specific or tissue-enriched patterns Cell type expression (Tabula Sapiens, HCA, etc.): - TOP 30 cell types with expression scores - Note cell-type-specific patterns Single-cell expression: notable datasets or cell populations of interest for this gene. ### Section 12: Disease associations For human gene ESR1, summarize disease associations. Mendelian / monogenic disease: - Diseases caused by mutations in ESR1: disease name, disease ID (OMIM/Orphanet/Mondo), inheritance pattern, evidence level - Include all directly linked conditions Phenotype associations: - Clinical phenotypes associated with the gene (HPO terms where known) - TOP 30 phenotype terms with HPO IDs Complex-disease / GWAS: - Traits and diseases significantly associated via GWAS: trait name, variant, effect size, study where known - TOP 30 GWAS associations
Executive summary
ESR1 encodes estrogen receptor alpha (ER-alpha, UniProt P03372), the primary mediator of estrogen signaling in humans and one of the most clinically important targets in oncology. Located on chromosome 6 (151,651,284–152,129,619 bp), it functions as a ligand-activated transcription factor with zinc finger DNA-binding and nuclear hormone receptor ligand-binding domains, directly activating or repressing at least 100 downstream target genes. Expression is highest in female reproductive tissues (oviduct, cervix, endometrium, breast epithelium) but extends broadly across 286 conditions. ESR1 is the target of major approved breast cancer therapeutics including tamoxifen (241 clinical trials), fulvestrant (418 trials), and letrozole (555 trials), with CYP2D6 pharmacogenomics critically affecting tamoxifen efficacy. GWAS links ESR1 variants to heel bone mineral density (p=2e-212), breast cancer susceptibility (p=5e-54), and cardiovascular traits, while rare loss-of-function mutations cause autosomal recessive estrogen resistance syndrome. The protein is exceptionally well-studied structurally, with 475 experimental PDB entries and an 8,546-partner STRING interaction network anchored by coactivators, BRCA1, SRC, and EGFR.
ESR1 — Reference
Cross-database identifier and functional mapping reference for ESR1.
Gene identifiers
- HGNC ID: HGNC:3467
- Approved symbol: ESR1
- Ensembl gene ID: ENSG00000091831
- NCBI Entrez Gene ID: 2099
- OMIM gene/locus ID: 133430
- Genomic location (GRCh38):
- Chromosome: 6
- Start position: 151,651,284 bp
- End position: 152,129,619 bp
- Strand: +
Transcript identifiers
Ensembl transcripts (18 total)
| Transcript ID | Biotype |
|---|---|
| ENST00000206249 | protein_coding |
| ENST00000338799 | protein_coding |
| ENST00000404742 | protein_coding |
| ENST00000406599 | protein_coding |
| ENST00000415488 | protein_coding |
| ENST00000427531 | protein_coding |
| ENST00000440973 | protein_coding |
| ENST00000443427 | protein_coding |
| ENST00000446550 | protein_coding |
| ENST00000456483 | protein_coding |
| ENST00000473497 | protein_coding_CDS_not_defined |
| ENST00000482101 | protein_coding_CDS_not_defined |
| ENST00000488573 | protein_coding_CDS_not_defined |
| ENST00000641399 | protein_coding_CDS_not_defined |
| ENST00000858333 | protein_coding |
| ENST00000858334 | protein_coding |
| ENST00000858335 | protein_coding |
| ENST00000947759 | protein_coding |
RefSeq mRNA transcripts (NM_ accessions)
| Accession | MANE Select |
|---|---|
| NM_000125 | ✓ Yes |
| NM_001122740 | No |
| NM_001122741 | No |
| NM_001122742 | No |
| NM_001291230 | No |
| NM_001291241 | No |
| NM_001328100 | No |
| NM_001385568 | No |
| NM_001385569 | No |
| NM_001385570 | No |
| NM_001385571 | No |
| NM_001385572 | No |
CCDS identifiers
| CCDS ID |
|---|
| CCDS5234 |
| CCDS87457 |
MANE Select/Canonical transcript exons: ENST00000206249 (NM_000125)
Total exon count: 8
| Exon ID | Start | End | Strand | Chromosome |
|---|---|---|---|---|
| ENSE00001877305 | 151,807,682 | 151,808,364 | + | 6 |
| ENSE00003705805 | 151,842,597 | 151,842,787 | + | 6 |
| ENSE00003721187 | 151,880,655 | 151,880,771 | + | 6 |
| ENSE00003743537 | 152,060,991 | 152,061,124 | + | 6 |
| ENSE00003736522 | 152,094,385 | 152,094,568 | + | 6 |
| ENSE00000813753 | 152,011,656 | 152,011,794 | + | 6 |
| ENSE00001128501 | 152,098,732 | 152,103,274 | + | 6 |
Protein identifiers
UniProt accessions
Canonical reviewed entry:
- P03372 — Estrogen receptor (ER-alpha)
Unreviewed entries:
- B0QYW7
- G4XH65
- H0Y4W6
- Q5T5H8
- Q9H2M1
- Q9H2M2
- Q9UE35
RefSeq protein accessions (NP_)
- NP_000116 — MANE Select canonical
- NP_001116212
- NP_001116213
- NP_001116214
- NP_001278159
- NP_001278170
- NP_001315029
- NP_001372497
- NP_001372498
Protein domains and families
| Identifier | Type | Database | Name |
|---|---|---|---|
| IPR000536 | Domain | InterPro | Nuclear hormone receptor, ligand-binding domain |
| IPR001292 | Family | InterPro | Estrogen receptor |
| IPR001628 | Domain | InterPro | Zinc finger, nuclear hormone receptor-type |
| IPR001723 | Family | InterPro | Nuclear hormone receptor |
| IPR013088 | Homologous superfamily | InterPro | Zinc finger, NHR/GATA-type |
| IPR024178 | Family | InterPro | Estrogen receptor/oestrogen-related receptor |
| IPR024736 | Domain | InterPro | Oestrogen-type nuclear receptor final C-terminal domain |
| IPR035500 | Homologous superfamily | InterPro | Nuclear hormone receptor-like domain superfamily |
| IPR046944 | Domain | InterPro | Estrogen receptor, N-terminal |
| IPR050200 | Family | InterPro | Nuclear hormone receptor family NR3 subfamily |
| PF00104 | Domain | Pfam | — |
| PF00105 | Domain | Pfam | — |
| PF02159 | Domain | Pfam | — |
| PF12743 | Domain | Pfam | — |
| SM00399 | Domain | SMART | (Zinc finger, nuclear hormone receptor-type) |
| SM00430 | Domain | SMART | (Nuclear hormone receptor, ligand-binding domain) |
| CD06949 | Domain | CDD | — |
| CD07171 | Domain | CDD | — |
Antibody availability
No antibody resources found in biobtree for ESR1. The standard biobtree antibody database does not contain entries mapping to this protein.
Structure
Experimental Structures: 475 total PDB entries
X-ray Crystallography
- Total count: 468 structures
- Resolution range: 1.15 – 3.1 Å
- Notable high-resolution structures:
- Highest resolution: 7B9R, 7B9T, 7BA8, 7BA9, 8BZC, 8BZW, 8C04 (1.15 Å)
- Typical range: 1.4 – 2.5 Å
- Ligand complexes: Predominantly ligand-binding domain (LBD) structures with various estrogens, selective estrogen receptor modulators (SERMs), selective estrogen receptor degraders (SERDs), and synthetic compounds
- Key regions covered: Ligand-binding domain, DNA-binding domain interactions with proteins and peptides
Solution NMR
- Total count: 4 structures
- Entries: 1HCP, 2LLO, 2LLQ, 5T0X
- Note: No X-ray resolution data; these represent solution structures of DNA-binding domain and calmodulin-binding peptide complexes
Predicted Structure: AlphaFold
- Model ID: P03372
- Confidence metric (pLDDT): 67.14 (global average)
- High confidence regions: 45% of the structure (pLDDT > 90)
- Interpretation: Moderate overall confidence with well-predicted structured domains; lower confidence in flexible regions typical of intrinsically disordered proteins
Cross-species orthologs
| Organism | Gene ID | Symbol |
|---|---|---|
| Mouse (Mus musculus) | 13982 | Esr1 |
| Rat (Rattus norvegicus) | 24890 | Esr1 |
| Zebrafish (Danio rerio) | 259252 | esr1 |
| Fruit fly (Drosophila melanogaster) | 38912 | ERR |
| Worm (C. elegans) | none | none |
| Yeast (S. cerevisiae) | none | none |
Clinical variants & AI predictions
ClinVar Summary
Total variants: ~217
Classification breakdown:
| Class | Count |
|---|---|
| Benign | 33 |
| Likely Benign | 32 |
| Uncertain Significance (VUS) | ~140 |
| Pathogenic | 2 |
| Likely Pathogenic | 0 |
| Risk Factor | 2 |
| Conflicting | 2 |
Top 30 Pathogenic/Likely Pathogenic variants (ranked by classification strength):
| ClinVar ID | HGVS Notation | Condition/Note |
|---|---|---|
| 16590 | NM_000125.4(ESR1):c.1339_1340delinsGC (p.Cys447Ala) | Pathogenic |
| 16592 | NM_000125.4(ESR1):c.469C>T (p.Arg157Ter) | Pathogenic |
Note: Only 2 pathogenic/likely pathogenic variants in current ClinVar database for ESR1. Remaining disease associations documented primarily as VUS (n=~140).
AlphaMissense Predictions
Total variants: 3,910
Likely pathogenic variants: 117+ (filtered subset shown)
Top 30 likely-pathogenic missense predictions:
| Variant | Protein Change | AlphaMissense Score |
|---|---|---|
| 6:151842697:T:C | C185R | 1.000 |
| 6:151842697:T:A | C185S | 1.000 |
| 6:151842697:T:G | C185G | 1.000 |
| 6:151842698:G:A | C185Y | 1.000 |
| 6:151842698:G:C | C185S | 1.000 |
| 6:151842698:G:T | C185F | 1.000 |
| 6:151842699:T:G | C185W | 1.000 |
| 6:151842706:T:A | C188S | 1.000 |
| 6:151842706:T:C | C188R | 1.000 |
| 6:151842707:G:A | C188Y | 1.000 |
| 6:151842707:G:C | C188S | 1.000 |
| 6:151842707:G:T | C188F | 1.000 |
| 6:151842708:C:G | C188W | 1.000 |
| 6:151842712:G:C | D190H | 1.000 |
| 6:151842713:A:C | D190A | 1.000 |
| 6:151842713:A:G | D190G | 1.000 |
| 6:151842713:A:T | D190V | 1.000 |
| 6:151842715:T:C | Y191H | 0.936 |
| 6:151842685:G:A | E181K | 0.952 |
| 6:151842684:G:C | K180N | 0.925 |
| 6:151842684:G:T | K180N | 0.925 |
| 6:151842686:A:T | E181V | 0.922 |
| 6:151842691:C:A | R183S | 0.984 |
| 6:151842692:G:C | R183P | 0.982 |
| 6:151842700:G:C | A186P | 0.996 |
| 6:151842701:C:A | A186E | 0.964 |
| 6:151842703:G:A | V187M | 0.999 |
| 6:151842703:G:C | V187L | 0.999 |
| 6:151842703:G:T | V187L | 0.999 |
| 6:151842704:T:A | V187E | 1.000 |
Splice Effect Predictions (SpliceAI)
Total predicted splice variants: 4,481
Top 30 high-confidence splice predictions (Delta score ≥ 0.8):
| Genomic Position | Effect Type | Delta Score |
|---|---|---|
| 6:151690665:G:GG | donor_gain | 1.00 |
| 6:151690595:TCC:T | donor_gain | 0.92 |
| 6:151690663:AAG:A | donor_loss | 0.98 |
| 6:151690664:AG:A | donor_loss | 0.98 |
| 6:151690665:G:A | donor_loss | 0.98 |
| 6:151690666:TAG:T | donor_loss | 0.98 |
| 6:151690669:G:GT | donor_loss | 0.81 |
| 6:151690596:C:A | donor_gain | 0.79 |
| 6:151690649:A:AG | donor_gain | 0.77 |
| 6:151690660:TTCAA:T | donor_gain | 0.84 |
| 6:151699907:A:G | donor_gain | 0.83 |
| 6:151698861:G:GT | donor_gain | 0.45 |
| 6:151701208:G:GT | donor_gain | 0.32 |
| 6:151690663:AA:A | donor_gain | 0.90 |
| 6:151690662:CAA:C | donor_gain | 0.67 |
| 6:151690662:CAAGT:C | donor_gain | 0.62 |
| 6:151697494:G:GT | donor_gain | 0.62 |
| 6:151690666:T:C | donor_gain | 0.62 |
| 6:151697479:A:AG | donor_gain | 0.63 |
| 6:151690668:GGTA:G | donor_loss | 0.94 |
| 6:151692211:ATTG:A | acceptor_gain | 0.52 |
| 6:151695288:CTA:C | acceptor_gain | 0.42 |
| 6:151697288:TAAAG:T | acceptor_gain | 0.41 |
| 6:151697289:AAAGA:A | acceptor_gain | 0.41 |
| 6:151698675:C:T | acceptor_gain | 0.46 |
| 6:151690791:T:A | acceptor_gain | 0.41 |
| 6:151690798:A:G | (no score) | — |
| 6:151690821:C:T | donor_gain | 0.53 |
| 6:151690863:AC:A | donor_gain | 0.66 |
| 6:151692211:ATT:A | acceptor_gain | 0.47 |
Pathways & Gene Ontology
Reactome Pathways
ESR1 participates in 17 Reactome pathways:
| ID | Pathway Name |
|---|---|
| R-HSA-1251985 | Nuclear signaling by ERBB4 |
| R-HSA-1257604 | PIP3 activates AKT signaling |
| R-HSA-2219530 | Constitutive Signaling by Aberrant PI3K in Cancer |
| R-HSA-383280 | Nuclear Receptor transcription pathway |
| R-HSA-4090294 | SUMOylation of intracellular receptors |
| R-HSA-5689896 | Ovarian tumor domain proteases |
| R-HSA-6811558 | PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling |
| R-HSA-8866910 | TFAP2 (AP-2) family regulates transcription of growth factors and their receptors |
| R-HSA-8931987 | RUNX1 regulates estrogen receptor mediated transcription |
| R-HSA-8939211 | ESR-mediated signaling |
| R-HSA-8939256 | RUNX1 regulates transcription of genes involved in WNT signaling |
| R-HSA-8939902 | Regulation of RUNX2 expression and activity |
| R-HSA-9009391 | Extra-nuclear estrogen signaling |
| R-HSA-9018519 | Estrogen-dependent gene expression |
| R-HSA-9841251 | Mitochondrial unfolded protein response (UPRmt) |
| R-HSA-9927418 | Developmental Lineage of Mammary Gland Luminal Epithelial Cells |
| R-HSA-9927426 | Developmental Lineage of Mammary Gland Alveolar Cells |
MSigDB Gene Sets
ESR1 is a member of 300+ MSigDB gene sets including:
- GO-based sets (Biological Process, Molecular Function, Cellular Component)
- Curated pathway sets (including PID, BIOCARTA, REACTOME subsets)
- Transcription factor targets
- miRNA targets
- Cancer-related signatures (breast cancer luminal, endocrine therapy resistance, ESR1-specific sets)
- Immunological signatures
- Developmental and reproductive process sets
Gene Ontology Annotations
Total: 80 GO terms annotated for ESR1 via UniProt
Biological Process (43 terms)
| Rank | GO ID | Term |
|---|---|---|
| 1 | GO:0030520 | Estrogen receptor signaling pathway |
| 2 | GO:0045944 | Positive regulation of transcription by RNA polymerase II |
| 3 | GO:0006357 | Regulation of transcription by RNA polymerase II |
| 4 | GO:0043401 | Steroid hormone receptor signaling pathway |
| 5 | GO:0043627 | Response to estrogen |
| 6 | GO:0071391 | Cellular response to estrogen stimulus |
| 7 | GO:0071392 | Cellular response to estradiol stimulus |
| 8 | GO:0032355 | Response to estradiol |
| 9 | GO:0007165 | Signal transduction |
| 10 | GO:0045893 | Positive regulation of DNA-templated transcription |
| 11 | GO:0030518 | Nuclear receptor-mediated steroid hormone signaling pathway |
| 12 | GO:0007200 | Phospholipase C-activating G protein-coupled receptor signaling pathway |
| 13 | GO:0051123 | RNA polymerase II preinitiation complex assembly |
| 14 | GO:0048863 | Stem cell differentiation |
| 15 | GO:0048146 | Positive regulation of fibroblast proliferation |
| 16 | GO:0006338 | Chromatin remodeling |
| 17 | GO:0000122 | Negative regulation of transcription by RNA polymerase II |
| 18 | GO:0045429 | Positive regulation of nitric oxide biosynthetic process |
| 19 | GO:0060749 | Mammary gland alveolus development |
| 20 | GO:0060750 | Epithelial cell proliferation involved in mammary gland duct elongation |
Molecular Function (25 terms)
| Rank | GO ID | Term |
|---|---|---|
| 1 | GO:0004879 | Nuclear receptor activity |
| 2 | GO:0030284 | Nuclear estrogen receptor activity |
| 3 | GO:0000981 | DNA-binding transcription factor activity, RNA polymerase II-specific |
| 4 | GO:0001228 | DNA-binding transcription activator activity, RNA polymerase II-specific |
| 5 | GO:0003700 | DNA-binding transcription factor activity |
| 6 | GO:0034056 | Estrogen response element binding |
| 7 | GO:0030331 | Nuclear estrogen receptor binding |
| 8 | GO:0001221 | Transcription coregulator binding |
| 9 | GO:0001223 | Transcription coactivator binding |
| 10 | GO:0001222 | Transcription corepressor binding |
| 11 | GO:0005496 | Steroid binding |
| 12 | GO:0000978 | RNA polymerase II cis-regulatory region sequence-specific DNA binding |
| 13 | GO:0003682 | Chromatin binding |
| 14 | GO:0008013 | Beta-catenin binding |
| 15 | GO:0008270 | Zinc ion binding |
| 16 | GO:0019899 | Enzyme binding |
| 17 | GO:0019901 | Protein kinase binding |
| 18 | GO:0042802 | Identical protein binding |
| 19 | GO:0005516 | Calmodulin binding |
| 20 | GO:0017025 | TBP-class protein binding |
Cellular Component (11 terms)
| Rank | GO ID | Term |
|---|---|---|
| 1 | GO:0005634 | Nucleus |
| 2 | GO:0005654 | Nucleoplasm |
| 3 | GO:0005737 | Cytoplasm |
| 4 | GO:0005829 | Cytosol |
| 5 | GO:0000785 | Chromatin |
| 6 | GO:0000791 | Euchromatin |
| 7 | GO:0005667 | Transcription regulator complex |
| 8 | GO:0016020 | Membrane |
| 9 | GO:0005886 | Plasma membrane |
| 10 | GO:0005794 | Golgi apparatus |
| 11 | GO:0032991 | Protein-containing complex |
Protein interactions & networks
Protein-Protein Interactions
Total Interaction Count:
- STRING: 8,546 interactions
- BioGRID: ~1,384 interactions
- IntAct: 392 interactions
TOP 30 STRING Interactions (Highest Confidence Scores)
| Rank | Gene Symbol | UniProt ID | STRING Score | Protein Name |
|---|---|---|---|---|
| 1 | NCOA3 | Q9Y6Q9 | 997 | Nuclear receptor coactivator 3 |
| 2 | SRC | P12931 | 996 | Proto-oncogene tyrosine-protein kinase Src |
| 3 | JUN | P05412 | 995 | Transcription factor Jun |
| 4 | BRCA1 | P38398 | 995 | Breast cancer type 1 susceptibility protein |
| 5 | FOS | P01100 | 994 | Protein c-Fos |
| 6 | IGF1R | P08069 | 994 | Insulin-like growth factor 1 receptor |
| 7 | CAV1 | Q03135 | 992 | Caveolin-1 |
| 8 | FOXA1 | P55317 | 990 | Hepatocyte nuclear factor 3-alpha |
| 9 | HSP90AA1 | P07900 | 988 | Heat shock protein HSP 90-alpha |
| 10 | NRIP1 | P48552 | 988 | Nuclear receptor-interacting protein 1 |
| 11 | NCOR1 | O75376 | 987 | Nuclear receptor corepressor 1 |
| 12 | HDAC1 | Q13547 | 987 | Histone deacetylase 1 |
| 13 | NCOA1 | Q15788 | 986 | Nuclear receptor coactivator 1 |
| 14 | GNA13 | Q14344 | 985 | Guanine nucleotide-binding protein subunit alpha-13 |
| 15 | HSP90AB1 | P08238 | 983 | Heat shock protein HSP 90-beta |
| 16 | CALM3 | P27482 | 981 | Calmodulin-like protein 3 |
| 17 | SP1 | P08047 | 979 | Transcription factor Sp1 |
| 18 | AR | P10275 | 979 | Androgen receptor |
| 19 | NCOA2 | Q15596 | 979 | Nuclear receptor coactivator 2 |
| 20 | CALML6 | Q8TD86 | 979 | Calmodulin-like protein 6 |
| 21 | DDX17 | Q92841 | 979 | ATP-dependent RNA helicase DDX17 |
| 22 | CALML4 | Q96GE6 | 979 | Calmodulin-like protein 4 |
| 23 | CALML5 | Q9NZT1 | 979 | Calmodulin-like protein 5 |
| 24 | EGFR | P00533 | 974 | Epidermal growth factor receptor |
| 25 | TP53 | P04637 | 974 | Cellular tumor antigen p53 |
| 26 | CCND1 | P24385 | 972 | G1/S-specific cyclin-D1 |
| 27 | PIK3R1 | P27986 | 971 | Phosphatidylinositol 3-kinase regulatory subunit alpha |
| 28 | ERBB2 | P04626 | 966 | Receptor tyrosine-protein kinase erbB-2 |
| 29 | IGF1 | P05019 | 964 | Insulin-like growth factor 1 |
| 30 | SHC1 | P29353 | 962 | SHC-transforming protein 1 |
Top IntAct High-Confidence Interactions:
| Partner Gene | Confidence Score | Interaction Type |
|---|---|---|
| BRCA1 | 0.810 | Direct interaction |
| PGR | 0.770 | Physical association |
| ARID5A | 0.630 | Physical association |
| GATA3 | 0.620 | Association |
| NCOA3 | 0.690 | Physical association |
| SRC | 0.850 | Association |
Top BioGRID Interactions: Major interacting partners identified through multiple experimental systems (Co-localization, Affinity Capture-Western, Reconstituted Complex, Biochemical Activity):
- Chromatin remodeling: POLR2A/B/C/D/E/F/G/H/I/J/K/L (RNA Polymerase II subunits)
- Coactivators: EP300, NCOA2, NCOA3
- Chromatin modifiers: HDAC3, ASCC1
- Nuclear hormone receptors: PGR (Progesterone receptor)
- DNA repair: BRCA1
- Signaling: SRC, SKP2
Protein Similarity
Structural/Embedding Similarity (ESM2) - TOP 20 Similar Proteins
| Rank | UniProt ID | Max Similarity | Avg Similarity | Protein Type |
|---|---|---|---|---|
| 1 | B3SV56 | 1.0000 | 0.9930 | Nuclear hormone receptor homolog |
| 2 | Q07917 | 1.0000 | 0.9935 | Hormone receptor |
| 3 | Q08E02 | 1.0000 | 0.9931 | Hormone receptor |
| 4 | G3LSH3 | 0.9987 | 0.9775 | Estrogen receptor-like |
| 5 | A0A0K0PU92 | 0.9999 | 0.9772 | Estrogen receptor variant |
| 6 | G8GTN7 | 0.9997 | 0.9768 | Nuclear receptor |
| 7 | A0A072VIM5 | 0.9984 | 0.9774 | Hormone receptor |
| 8 | A2CIR7 | 0.9980 | 0.9772 | Estrogen receptor ortholog |
| 9 | O13012 | 0.9977 | 0.9953 | Nuclear hormone receptor |
| 10 | P70662 | 1.0000 | 0.9823 | Hormone receptor |
| 11 | Q92830 | 0.9999 | 0.9859 | Nuclear receptor |
| 12 | Q9JHD2 | 0.9999 | 0.9860 | Estrogen receptor |
| 13 | P51449 | 0.9999 | 0.9906 | Hormone receptor |
| 14 | Q14995 | 0.9992 | 0.9906 | Nuclear receptor |
| 15 | O15350 | 0.9999 | 0.9879 | Estrogen receptor-related |
| 16 | Q15406 | 0.9999 | 0.9942 | Nuclear hormone receptor |
| 17 | Q29040 | 0.9998 | 0.9956 | Hormone receptor ortholog |
| 18 | O42132 | 0.9998 | 0.9945 | Nuclear receptor |
| 19 | O42252 | 0.9998 | 0.9816 | Hormone receptor |
| 20 | P06211 | 0.9999 | 0.9953 | Progesterone receptor-related |
Sequence Homology (DIAMOND) - TOP 20 Homologous Proteins
| Rank | UniProt ID | Identity (%) | Bitscore | Protein Description |
|---|---|---|---|---|
| 1 | A7X8B3 | 99.50 | 1707 | Estrogen receptor alpha ortholog |
| 2 | A7X8B5 | 99.50 | 1705 | ER-alpha variant |
| 3 | A7X8B7 | 99.10 | 1701 | Estrogen receptor homolog |
| 4 | Q3YC04 | 99.20 | 1795 | Hormone receptor protein |
| 5 | Q4JM28 | 99.60 | 1812 | Nuclear receptor protein |
| 6 | P08235 | 98.70 | 1781 | Androgen receptor-related |
| 7 | P06401 | 98.60 | 1692 | Glucocorticoid receptor homolog |
| 8 | A7X8C2 | 97.10 | 1657 | ER variant |
| 9 | Q00175 | 95.00 | 1607 | Nuclear hormone receptor |
| 10 | P79686 | 99.50 | 1499 | Estrogen receptor variant |
| 11 | O13186 | 99.70 | 1499 | Hormone receptor ortholog |
| 12 | O46567 | 99.70 | 1500 | ER-alpha |
| 13 | P04150 | 99.40 | 1506 | Progesterone receptor |
| 14 | Q29131 | 93.50 | 1652 | Nuclear receptor protein |
| 15 | A7X8B9 | 97.40 | 1680 | ER variant |
| 16 | A7X8D2 | 98.00 | 1697 | Estrogen receptor |
| 17 | A7X8C4 | 98.30 | 1685 | ER-alpha ortholog |
| 18 | P79269 | 99.40 | 1498 | Nuclear hormone receptor |
| 19 | P06186 | 96.80 | 1501 | Steroid hormone receptor |
| 20 | O88275 | 99.60 | 1007 | Hormone receptor homolog |
Transcription factor regulatory data
ESR1 (Estrogen Receptor Alpha) is a transcription factor.
DNA Binding Motifs (JASPAR)
| Motif ID | Classification | Species | Collection |
|---|---|---|---|
| MA0112.1 | Nuclear receptors with C4 zinc fingers; Steroid hormone receptors (NR3) | Xenopus laevis, Xenopus tropicalis, Gallus gallus, Homo sapiens, Bos taurus, Oryctolagus cuniculus, Mus musculus, Rattus norvegicus | CORE |
| MA0112.2 | Nuclear receptors with C4 zinc fingers; Steroid hormone receptors (NR3) | Homo sapiens | CORE |
| MA0112.3 | Nuclear receptors with C4 zinc fingers; Steroid hormone receptors (NR3) | Homo sapiens | CORE |
| MA0112.4 | Nuclear receptors with C4 zinc fingers; Steroid hormone receptors (NR3) | Homo sapiens | CORE |
Downstream Targets
Total count: 100 genes
Top 30 targets (regulation type and evidence confidence):
| # | Target | Regulation | Evidence |
|---|---|---|---|
| 1 | AICDA | Activation | High |
| 2 | CCND1 | Activation | High |
| 3 | CDC25A | Activation | High |
| 4 | CDKN1A | Activation | High |
| 5 | BMP2 | Activation | High |
| 6 | CYP19A1 | Activation | High |
| 7 | CRABP2 | Activation | — |
| 8 | DACH1 | Activation | High |
| 9 | DCT | Activation | High |
| 10 | CYP7B1 | Activation | High |
| 11 | CRHBP | Activation | High |
| 12 | AMH | Activation | High |
| 13 | BCL2 | Activation | High |
| 14 | BIRC5 | Activation | High |
| 15 | BTG2 | Repression | High |
| 16 | CAV1 | Repression | High |
| 17 | CD24 | Repression | High |
| 18 | CDKN1B | Repression | High |
| 19 | CDKN1C | Repression | High |
| 20 | CRH | Repression | High |
| 21 | CYP1A1 | Repression | High |
| 22 | CYP2C19 | Repression | High |
| 23 | CYP2C9 | Repression | High |
| 24 | CCL2 | Activation | — |
| 25 | CCL5 | Activation | Low |
| 26 | CCNA2 | Activation | Low |
| 27 | ACHE | — | High |
| 28 | ACKR3 | — | High |
| 29 | ACSBG1 | — | High |
| 30 | ADA | — | High |
Upstream Regulators of ESR1
| Regulator TF | Regulation Type | Evidence Confidence |
|---|---|---|
| DNMT1 | Unknown | High |
| ARID5A | — | High |
| AHR | — | High |
| AP1 | — | High |
| DBP | — | High |
| E2F4 | Unknown | High |
| BRCA1 | Activation | — |
| BARD1 | Activation | — |
| AR | Repression | Low |
| AIP | Repression | — |
| CEBPD | Repression | — |
| ATF6 | — | Low |
| DNMT3A | — | Low |
| DNMT3B | — | Low |
| ARNT | Unknown | — |
| CREB1 | Unknown | — |
| BARX2 | Unknown | — |
Drug & pharmacology data
ESR1 (Estrogen Receptor 1) is a well-characterized and major drug target with extensive clinical validation.
Targeting Molecules
- Total count: 4,508 in ChEMBL | 141 in DrugBank
Top 30 by Development Phase (approved Phase 4 drugs):
| Molecule ID | Name | Mechanism | Phase | Clinical Trials |
|---|---|---|---|---|
| CHEMBL83 | Tamoxifen | Selective estrogen receptor modulator (antagonist) | 4 | 241 |
| CHEMBL1358 | Fulvestrant | ER antagonist/degrader | 4 | 418 |
| CHEMBL1444 | Letrozole | Aromatase inhibitor (indirect) | 4 | 555 |
| CHEMBL81 | Raloxifene | Selective estrogen receptor modulator | 4 | 54 |
| CHEMBL1399 | Anastrozole | Aromatase inhibitor (indirect) | 4 | 278 |
| CHEMBL1200374 | Exemestane | Aromatase inhibitor (indirect) | 4 | 233 |
| CHEMBL1116 | Raloxifene HCl | SERM | 4 | (counted with CHEMBL81) |
Phase 3:
- CHEMBL1093458 | Endoxifen | Active metabolite of tamoxifen | 3
- CHEMBL1213583 | Gestodene | Progestin/ER modulator | 3
Clinical Trials (Top 20 by activity)
Letrozole (555 trials), Fulvestrant (418 trials), Tamoxifen (241 trials), Anastrozole (278 trials), and Exemestane (233 trials) collectively represent the largest clinical development portfolio. Primary indications include breast cancer treatment/prevention, postmenopausal osteoporosis, and hormone-sensitive conditions.
Pharmacogenomics
Known Drug-Gene Interactions Affecting Response:
Critical Metabolic Gene - CYP2D6 (Tamoxifen):
- FDA Label: Informative PGx
- Swissmedic Label: Actionable PGx
- Poor metabolizers show reduced conversion of tamoxifen to active metabolite (endoxifen), associated with worse outcomes in breast cancer
- CPIC, CPNDS, DPWG dosing guidelines available
Secondary Metabolic Genes (Tamoxifen):
- CYP3A4: Involved in metabolism; variant annotations available
- CYP2C19: Clinical and pathway associations
- ABCB1 (MDR1): Transporter; affects drug bioavailability
- CYP19A1 (Aromatase): Pharmacodynamic interaction
Pharmacodynamic Genes:
- ESR1 variants: Associated with treatment response (279 variant annotations in PharmGKB)
- ESR2: Secondary ER; clinical relevance
- PGR (Progesterone Receptor): Predictive of hormone sensitivity
- NCOA1 (Coactivator): Associated with clinical outcomes
- F2, F5: Thrombosis risk (FDA-labeled; relevant for SERMs like raloxifene)
Available Dosing Guidelines: CPIC, CPNDS (Canadian), DPWG (Dutch) provide CYP2D6-based recommendations for tamoxifen; testing level = “Testing Required” per FDA label.
Expression profiles
Tissue expression (Bgee)
ESR1 shows ubiquitous expression breadth across 286 conditions, with 216 present calls and a maximum expression score of 97.49. Strong enrichment in reproductive and endocrine tissues.
| Rank | Tissue | Expression Score | Quality |
|---|---|---|---|
| 1 | Oviduct epithelium | 97.49 | Gold |
| 2 | Cervix epithelium | 96.89 | Gold |
| 3 | Mammalian vulva | 96.85 | Gold |
| 4 | Endometrium | 96.64 | Gold |
| 5 | Uterine cervix | 96.04 | Gold |
| 6 | Cervix squamous epithelium | 95.98 | Gold |
| 7 | Fallopian tube | 95.94 | Gold |
| 8 | Endocervix | 95.16 | Gold |
| 9 | Right uterine tube | 94.72 | Gold |
| 10 | Uterus | 94.53 | Gold |
| 11 | Ectocervix | 94.34 | Gold |
| 12 | Epithelium of mammary gland | 94.10 | Gold |
| 13 | Mammary duct | 93.85 | Gold |
| 14 | Body of uterus | 93.61 | Gold |
| 15 | Vagina | 93.35 | Gold |
| 16 | Caput epididymis | 92.43 | Gold |
| 17 | Germinal epithelium of ovary | 91.68 | Gold |
| 18 | Calcaneal tendon | 91.13 | Gold |
| 19 | Urethra | 90.87 | Gold |
| 20 | Myometrium | 90.85 | Gold |
| 21 | Tibia | 90.56 | Gold |
| 22 | Mammary gland | 89.63 | Gold |
| 23 | Thoracic mammary gland | 89.62 | Gold |
| 24 | Left uterine tube | 89.21 | Gold |
| 25 | Adult organism | 88.52 | Gold |
| 26 | Female reproductive system | 88.11 | Gold |
| 27 | Nipple | 86.20 | Gold |
| 28 | Tendon | 85.42 | Gold |
| 29 | Decidua | 83.72 | Gold |
| 30 | Right lobe of liver | 83.44 | Gold |
Pattern: Dominant expression in female reproductive tissues (uterus, ovary, fallopian tubes, cervix, vagina, vulva) and breast epithelium, consistent with estrogen receptor function. Secondary expression in bone, tendon, and urogenital tissues.
Cell type expression (Bgee)
ESR1 identified in multiple cell types across reproductive and immune compartments:
- Sperm
- Male germ cells
- Bone marrow cells
- Endometrial stromal cells (stromal cells of endometrium)
- Granulocytes
- Leukocytes (including monocytes, mononuclear leukocytes)
Single-cell expression datasets
Four single-cell experiments in SCXA:
| Experiment | Tissue | Cell Count | Context |
|---|---|---|---|
| E-HCAD-38 | Human proximal epididymis | 17,692 | Single-cell atlas with cell-type specific ESR1 expression in reproductive epithelium |
| E-MTAB-11268 | Human hypertrophied heart | 64,898 | Expression in cardiac cell populations relevant to sex-hormone-dependent cardiac remodeling |
Single-cell summary: ESR1 expressed as a marker gene in 4 experiments across 177 cell clusters, with maximum mean expression of 1,321.93 transcripts/cell (indicating strong expression in specific populations), average mean expression of 32.06.
Disease associations
Mendelian / Monogenic Disease
ESR1 mutations cause a single well-characterized autosomal recessive disorder:
| Disease | Disease IDs | Inheritance | Evidence Level |
|---|---|---|---|
| Estrogen Resistance Syndrome | OMIM:615363, Orphanet:785, MONDO:0014148 | Autosomal recessive | Limited/Supportive (GenCC) |
Estrogen resistance syndrome (ERS) is a rare disorder of estrogen signaling characterized by clinical resistance to estrogen hormones, leading to reproductive and metabolic abnormalities.
Phenotype Associations
TOP 30 HPO phenotypes associated with ESR1:
- HP:0000006 – Autosomal dominant inheritance
- HP:0000007 – Autosomal recessive inheritance
- HP:0000013 – Hypoplasia of the uterus
- HP:0000098 – Tall stature
- HP:0000147 – Polycystic ovaries
- HP:0000613 – Photophobia
- HP:0000786 – Primary amenorrhea
- HP:0000823 – Delayed puberty
- HP:0000834 – Abnormality of the adrenal glands
- HP:0000837 – Increased circulating gonadotropin level
- HP:0000842 – Hyperinsulinemia
- HP:0000938 – Osteopenia
- HP:0000939 – Osteoporosis
- HP:0000956 – Acanthosis nigricans
- HP:0001061 – Acne
- HP:0001442 – Typified by somatic mosaicism
- HP:0001548 – Overgrowth
- HP:0001677 – Coronary artery atherosclerosis
- HP:0001952 – Glucose intolerance
- HP:0002013 – Vomiting
- HP:0002018 – Nausea
- HP:0002077 – Migraine with aura
- HP:0002083 – Migraine without aura
- HP:0002183 – Phonophobia
- HP:0002574 – Episodic abdominal pain
- HP:0002663 – Delayed epiphyseal ossification
- HP:0002750 – Delayed skeletal maturation
- HP:0003002 – Breast carcinoma
- HP:0003117 – Abnormal circulating hormone concentration
- HP:0003187 – Breast hypoplasia
Complex Disease / GWAS
TOP 30 GWAS associations (ranked by p-value significance):
| Rank | Trait | P-value | Study |
|---|---|---|---|
| 1 | Heel bone mineral density | 2e-212 | GCST006433 |
| 2 | Heel bone mineral density | 1e-138 | GCST006979 |
| 3 | Heel bone mineral density | 9e-130 | GCST009120 |
| 4 | Height | 2e-24 | GCST002647 |
| 5 | Breast cancer | 4e-28 | GCST003845 |
| 6 | Pulse pressure | 8e-28 | GCST004278 |
| 7 | Pulse pressure | 6e-32 | GCST007269 |
| 8 | Birth weight | 1e-28 | GCST008362 |
| 9 | Appendicular lean mass | 1e-37 | GCST90000025 |
| 10 | Age at first sexual intercourse | 8e-38 | GCST90000047 |
| 11 | Heel bone mineral density | 7e-35 | GCST006288 |
| 12 | Breast cancer | 5e-54 | GCST004988 |
| 13 | Heel bone mineral density (variance) | 5e-14 | GCST009115 |
| 14 | Bone properties (heel) | 7e-15 | GCST002333 |
| 15 | Breast size | 2e-16 | GCST006655 |
| 16 | Age at first birth | 1e-10 | GCST003795 |
| 17 | Body fat distribution (trunk fat ratio) | 1e-14 | GCST007294 |
| 18 | Systolic blood pressure | 3e-12 | GCST007267 |
| 19 | Diastolic blood pressure | 9e-11 | GCST007268 |
| 20 | Waist-to-hip ratio adjusted for BMI | 3e-09 | GCST90020025 |
| 21 | Bone mineral density (spine) | 6e-11 | GCST000494 |
| 22 | Bone mineral density (hip) | 2e-10 | GCST000495 |
| 23 | Sudden cardiac arrest | 7e-10 | GCST001099 |
| 24 | Anxiety | 1e-09 | GCST009837 |
| 25 | Hip circumference adjusted for BMI | 1e-09 | GCST012227 |
| 26 | Endometriosis | 3e-07 | GCST004549 |
| 27 | Developmental language disorder | 3e-06 | GCST003396 |
| 28 | Alcohol dependence | 8e-06 | GCST000432 |
| 29 | Smoking status (current vs former) | 5e-07 | GCST003778 |
| 30 | Obesity-related traits | 3e-06 | GCST001762 |
Key observations: ESR1 shows strongest associations with bone mineral density (particularly heel BMD), breast cancer susceptibility, and height. Significant associations also exist for cardiovascular traits (blood pressure, pulse pressure), reproductive timing (age at first birth/sexual intercourse), and metabolic traits (body composition, glucose tolerance). These reflect ESR1’s role as the primary estrogen receptor in human physiology.