GPER1

Summary

GPER1 (G protein-coupled estrogen receptor 1, HGNC:4485) is a protein-coding gene on chromosome 7p22.3, encoding G-protein coupled estrogen receptor 1 (Q99527). G-protein coupled estrogen receptor that binds to 17-beta-estradiol (E2) with high affinity, leading to rapid and transient activation of numerous intracellular signaling pathways.

This gene encodes a multi-pass membrane protein that localizes to the endoplasmic reticulum and a member of the G-protein coupled receptor 1 family. This receptor binds estrogen and activates multiple downstream signaling pathways, leading to stimulation of adenylate cyclase and an increase in cyclic AMP levels, while also promoting intracellular calcium mobilization and synthesis of phosphatidylinositol 3,4,5-trisphosphate in the nucleus. This protein therefore plays a role in the rapid nongenomic signaling events widely observed following stimulation of cells and tissues with estrogen. This receptor has been shown to play a role in diverse biological processes, including bone and nervous system development, metabolism, cognition, male fertility and uterine function.

Source: NCBI Gene 2852 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 3 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001098201

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4485
Approved symbol	GPER1
Name	G protein-coupled estrogen receptor 1
Location	7p22.3
Locus type	gene with protein product
Status	Approved
Aliases	FEG-1, GPCR-Br, LERGU, LERGU2, DRY12, LyGPR, CEPR
Ensembl gene	ENSG00000164850
Ensembl biotype	protein_coding
OMIM	601805
Entrez	2852

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 17 protein_coding

ENST00000297469, ENST00000397088, ENST00000397092, ENST00000401670, ENST00000413368, ENST00000853504, ENST00000853505, ENST00000853506, ENST00000853507, ENST00000853508, ENST00000853509, ENST00000853510, ENST00000853511, ENST00000853512, ENST00000853513, ENST00000964574, ENST00000964575

RefSeq mRNA: 3 — MANE Select: NM_001098201 NM_001039966, NM_001098201, NM_001505

CCDS: CCDS5322

Canonical transcript exons

ENST00000397088 — 2 exons

Exon	Start	End
ENSE00001527256	1088113	1088321
ENSE00001919675	1091407	1093810

Expression profiles

Bgee: expression breadth ubiquitous, 205 present calls, max score 88.17.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.7246 / max 102.4876, expressed in 1153 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
76914	2.3565	573
76913	0.9638	453
76915	0.7024	389
76910	0.6823	374
76912	0.5359	304
76911	0.4012	210
76916	0.0825	55

Top tissues by expression

282 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
body of stomach	UBERON:0001161	88.17	gold quality
middle frontal gyrus	UBERON:0002702	87.64	gold quality
fundus of stomach	UBERON:0001160	87.49	gold quality
frontal pole	UBERON:0002795	87.30	silver quality
paraflocculus	UBERON:0005351	87.00	silver quality
tendon of biceps brachii	UBERON:0008188	86.89	gold quality
right lobe of liver	UBERON:0001114	85.33	gold quality
stomach	UBERON:0000945	85.20	gold quality
apex of heart	UBERON:0002098	85.13	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.80	gold quality
right adrenal gland cortex	UBERON:0035827	82.56	gold quality
endometrium epithelium	UBERON:0004811	82.08	silver quality
putamen	UBERON:0001874	81.67	gold quality
cardia of stomach	UBERON:0001162	80.83	gold quality
metanephros cortex	UBERON:0010533	80.83	gold quality
medial globus pallidus	UBERON:0002477	80.80	silver quality
right adrenal gland	UBERON:0001233	80.70	gold quality
left adrenal gland cortex	UBERON:0035825	80.70	gold quality
liver	UBERON:0002107	80.65	gold quality
adrenal cortex	UBERON:0001235	80.27	gold quality
left adrenal gland	UBERON:0001234	80.26	gold quality
endothelial cell	CL:0000115	79.55	gold quality
amygdala	UBERON:0001876	79.53	gold quality
popliteal artery	UBERON:0002250	78.73	gold quality
cingulate cortex	UBERON:0003027	78.73	gold quality
tibial artery	UBERON:0007610	78.72	gold quality
anterior cingulate cortex	UBERON:0009835	78.69	gold quality
caudate nucleus	UBERON:0001873	78.59	gold quality
right frontal lobe	UBERON:0002810	78.53	gold quality
mucosa of stomach	UBERON:0001199	78.41	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.86
E-MTAB-6678	no	2.42

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets.

Target	Regulation
CCNB1	Repression
CCND1	Activation
CDKN1A	Activation

Upstream regulators (CollecTRI, top): AP1, ESR1, FOS, HIF1A, PITX2, RUNX2, TFAP2C

miRNA regulators (miRDB)

22 targeting GPER1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-1303	99.65	69.77	1662
HSA-MIR-3679-3P	99.64	69.88	1599
HSA-MIR-4316	99.37	65.75	1360
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6893-5P	99.31	66.25	2119
HSA-MIR-504-3P	99.30	67.18	1745
HSA-MIR-296-3P	99.21	66.56	474
HSA-MIR-4279	99.19	66.70	2437
HSA-MIR-3074-5P	98.82	66.56	1414
HSA-MIR-3135B	98.61	65.33	1470
HSA-MIR-3944-5P	98.50	67.55	997
HSA-MIR-4691-3P	98.11	66.83	1204
HSA-MIR-4659B-5P	98.03	66.84	979
HSA-MIR-4659A-5P	98.03	66.42	819
HSA-MIR-6787-5P	97.54	63.85	457
HSA-MIR-6849-3P	97.25	64.57	1371
HSA-MIR-764	94.16	64.85	656

Literature-anchored findings (GeneRIF, showing 40)

• estrogen transactivates the epidermal growth factor receptor (EGFR) to MAP K signaling axis via GPR30;implications for breast cancer biology (PMID:11897506)
• orphan receptor GPR30 is important for the inhibitory effect of progestin on mammary gland growth (PMID:12193550)
• results suggest that progestin-induced ERK inactivation is mediated through G protein-coupled receptor 30 (PMID:12446589)
• The G protein-coupled receptor GPR30 mediates c-fos up-regulation by 17beta-estradiol, genistrin and quercetin in breast cancer cells. (PMID:15090535)
• GPR30, an orphan receptor unrelated to nuclear estrogen receptors, has all the binding and signaling characteristics of a membrane estrogen receptor (PMID:15539556)
• GPR30 is localized to the endoplasmic reticulum where it specifically binds estrogen and estrogen derivatives; GPR30 represents an intracellular transmembrane estrogen receptor that may contribute to normal estrogen physiology as well as pathophysiology (PMID:15705806)
• GPR30 expression is downregulated in infiltrating ductal carcinoma of the breast; GPR30 is preferentially co-expressed with ER and/or PR but is lowly expressed in HER-2/neu(+) tumors (PMID:17638621)
• a relationship between GPR30 expression and age may underlie the observed pubertal decline in the GPR30 level (PMID:17878253)
• GPR30 has a role in breast tumor metastasis and transactivation of the epidermal growth factor receptor (PMID:18289622)
• The action of EGF may include the up-regulation of GPR30 in facilitating a stimulatory role of estrogen, even in ER-negative breast tumor cells. (PMID:18467441)
• In transiently transfected cells as well as cells endogenously expressing GPR30, we confirmed that the receptor localized to the endoplasmic reticulum (PMID:18566127)
• GPR30 transcripts are expressed in human skin dermis, but barely detectable in epidermis or appendages. GPR30 mRNA levels are not altered by topical 17beta-estradiol treatment. (PMID:18794456)
• activation of GPR30 by OHT also induces CTGF in fibroblasts from breast tumour biopsies, these pathways may be involved in promoting aggressive behaviour of breast tumours in response to endogenous oestrogens or to OHT being used for endocrine therapy. (PMID:19153601)
• novel roles for GPER in protecting from cardiovascular disease and obesity (PMID:19179659)
• Regulation of estrogen-mediated fibronectin matrix assembly and epidermal growth factor receptor transactivation by GPR30. (PMID:19342448)
• GPR30-mediated non-genomic signaling may play an important role in endometrial cancer. (PMID:19432902)
• GPR30 increases local concentrations of estrogen and mediates the proliferative effects of synthetic estrogens such as tamoxifen, in promoting endometriosis and endometrial cancers. (PMID:19549922)
• Results support the role of GPR30 in breast cancer and encourage functional studies on the molecular mechanisms underlying the association of the GPR30 polymorphisms rs11544331, rs3808350, and rs3808351 with progesterone receptor status and tumor growth. (PMID:19744559)
• G protein-coupled receptor 30 expression is up-regulated by EGF and TGF alpha in estrogen receptor alpha-positive cancer cells (PMID:19749156)
• mediates a wide range of responses to estrogen in a large variety of cell types (PMID:19767412)
• The majority of inflammatory breast cancer tumors are GPR30-positive (PMID:19902352)
• This data suggests the important role of GPR30/EGFR receptor signaling in the development of tamoxifen resistance (PMID:19911269)
• Data show that GPR30 antagonizes growth of ERalpha-positive breast cancer and may represent a new target to combat this disease. (PMID:20086172)
• Results demonstrated that previously reported activities of GPR30 in response to estrogen were through its ability to induce ER-alpha36 expression. (PMID:20197310)
• Binding of G-1 compound to GPR30 in PC-3 prostate cancer cells is followed by sustained activation of Erk1/2 and a c-jun/c-fos-dependent upregulation of p21, resulting in the arrest of PC-3 growth at the G(2) phase. (PMID:20203690)
• Data show that GPER-1 mediate the regulation of ERRalpha gene expression by estrogen receptor agonists and antagonists in SKBR3 breast cancer cells. (PMID:20211987)
• G protein-coupled estrogen receptor 1 (GPER, GPR 30) in normal human endometrium and early pregnancy decidua. (PMID:20508064)
• Investigated both mRNA and protein expression of GPER in the rat and human heart. The role of GPER in estrogen protection against ischaemic stress in the rat heart was also assessed. (PMID:20596598)
• GPR30 promotes the progress of estrogen-related tumors through mitogen-activated protein kinase (MAPK) signaling pathways (PMID:20960099)
• GPR30 may be involved in the invasion and metastasis of epithelial ovarian carcinoma. (PMID:21170498)
• ERalpha, ERbeta and GPER1/GPR30 are involved in preventing beta-cell apoptosis, impeding the loss of critical beta-cell mass. (PMID:21196169)
• HIF-1alpha-responsive elements located within the promoter region of GPER are involved in hypoxia-dependent transcription of GPER, which requires the ROS-induced activation of EGFR/ERK signaling (PMID:21266576)
• lower in endometrium of polycystic ovary syndrome group compared to controls (PMID:21269226)
• The GPR30 protein expression was detected at high level in all intratubular germ cell tumours, seminomas, and embryonal carcinomas, whereas in teratomas the expression was low. (PMID:21278491)
• the subcellular localization pattern of GPR30 in different tissues (PMID:21354433)
• GRp30-activated membrane estrogen receptors mediate increased contractility of the human myometrium. (PMID:21427217)
• High GPR30 is associated with tamoxifen resistance in breast cancer. (PMID:21607586)
• GPR30 is more sensitive, but less specific than mesothelin for pancreatic adenocarcinoma (PMID:21632639)
• GPER activation relaxes coronary artery smooth muscle by increasing potassium efflux via BK(Ca) channels and requires an intact cellular signaling mechanism. (PMID:21791623)
• Results suggest GPER is expressed in cytoplasm of non-neoplastic testes and neoplastic testes (including granuloma, Sertoli cell tumor, Leydig cell tumor, seminoma, and embryonal carcinoma). (PMID:21974818)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	gper1	ENSDARG00000074661
mus_musculus	Gper1	ENSMUSG00000053647
rattus_norvegicus	Gper1	ENSRNOG00000001287

Paralogs (1): GPR182 (ENSG00000166856)

Protein

Protein identifiers

G-protein coupled estrogen receptor 1 — Q99527 (reviewed: Q99527)

Alternative names: Chemoattractant receptor-like 2, Flow-induced endothelial G-protein coupled receptor 1, G protein-coupled estrogen receptor 1, G-protein coupled receptor 30, GPCR-Br, IL8-related receptor DRY12, Lymphocyte-derived G-protein coupled receptor, Membrane estrogen receptor

All UniProt accessions (2): C9J3W2, Q99527

UniProt curated annotations — full annotation on UniProt →

Function. G-protein coupled estrogen receptor that binds to 17-beta-estradiol (E2) with high affinity, leading to rapid and transient activation of numerous intracellular signaling pathways. Stimulates cAMP production, calcium mobilization and tyrosine kinase Src inducing the release of heparin-bound epidermal growth factor (HB-EGF) and subsequent transactivation of the epidermal growth factor receptor (EGFR), activating downstream signaling pathways such as PI3K/Akt and ERK/MAPK. Mediates pleiotropic functions among others in the cardiovascular, endocrine, reproductive, immune and central nervous systems. Has a role in cardioprotection by reducing cardiac hypertrophy and perivascular fibrosis in a RAMP3-dependent manner. Regulates arterial blood pressure by stimulating vasodilation and reducing vascular smooth muscle and microvascular endothelial cell proliferation. Plays a role in blood glucose homeostasis contributing to the insulin secretion response by pancreatic beta cells. Triggers mitochondrial apoptosis during pachytene spermatocyte differentiation. Stimulates uterine epithelial cell proliferation. Enhances uterine contractility in response to oxytocin. Contributes to thymic atrophy by inducing apoptosis. Attenuates TNF-mediated endothelial expression of leukocyte adhesion molecules. Promotes neuritogenesis in developing hippocampal neurons. Plays a role in acute neuroprotection against NMDA-induced excitotoxic neuronal death. Increases firing activity and intracellular calcium oscillations in luteinizing hormone-releasing hormone (LHRH) neurons. Inhibits early osteoblast proliferation at growth plate during skeletal development. Inhibits mature adipocyte differentiation and lipid accumulation. Involved in the recruitment of beta-arrestin 2 ARRB2 at the plasma membrane in epithelial cells. Also functions as a receptor for aldosterone mediating rapid regulation of vascular contractibility through the PI3K/ERK signaling pathway. Involved in cancer progression regulation. Stimulates cancer-associated fibroblast (CAF) proliferation by a rapid genomic response through the EGFR/ERK transduction pathway. Associated with EGFR, may act as a transcription factor activating growth regulatory genes (c-fos, cyclin D1). Promotes integrin alpha-5/beta-1 and fibronectin (FN) matrix assembly in breast cancer cells.

Subunit / interactions. Homodimer. Heterodimer; heterodimerizes with other G-protein-coupled receptor (GPCRs) like CRHR1, HTR1A and PAQR8. Interacts (via C-terminus tail motif) with DLG4 (via N-terminus tandem pair of PDZ domains); the interaction is direct and induces the increase of GPER1 protein levels residing at the plasma membrane surface in a estradiol-independent manner. Interacts with RAMP3; the interaction confers proper subcellular localization and function in cardioprotection. Interacts with KRT7 and KRT8. Interacts with EGFR; the interaction increases after agonist-induced stimulation in cancer-associated fibroblasts (CAF). Interacts with EGFR and ESR1.

Subcellular location. Nucleus. Cytoplasm. Perinuclear region. Cytoskeleton. Cell membrane. Basolateral cell membrane. Cytoplasmic vesicle membrane. Early endosome. Recycling endosome. Golgi apparatus membrane. Golgi apparatus. trans-Golgi network. Endoplasmic reticulum membrane. Cell projection. Dendrite. Dendritic spine membrane. Axon. Postsynaptic density. Mitochondrion membrane.

Tissue specificity. Expressed in placenta, endothelial and epithelial cells, non laboring and laboring term myometrium, fibroblasts and cancer-associated fibroblasts (CAF), prostate cancer cells and invasive adenocarcinoma (at protein level). Ubiquitously expressed, but is most abundant in placenta. In brain regions, expressed as a 2.8 kb transcript in basal forebrain, frontal cortex, thalamus, hippocampus, caudate and putamen.

Post-translational modifications. Ubiquitinated; ubiquitination occurs at the plasma membrane and leads to proteasome-mediated degradation. Glycosylated.

Induction. Up-regulated by EGF and TGF-alpha in endometrial, ovarian and breast tumor cells. Up-regulated by progestin and by phorbol 12-myristate 13-acetate (PMA) in breast cancer cell lines.

Miscellaneous. Does not bind estradiol according to PubMed:18566127 and PubMed:16645038.

Similarity. Belongs to the G-protein coupled receptor 1 family.

RefSeq proteins (3): NP_001035055, NP_001091671, NP_001496 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain
IPR047143	GPER1-like	Family

Pfam: PF00001

UniProt features (47 total): helix 11, sequence conflict 10, topological domain 8, transmembrane region 7, glycosylation site 3, turn 3, chain 1, modified residue 1, disulfide bond 1, sequence variant 1, strand 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
8XOF	ELECTRON MICROSCOPY	2.6
8XOG	ELECTRON MICROSCOPY	2.9
8XOJ	ELECTRON MICROSCOPY	3.1
8XOH	ELECTRON MICROSCOPY	3.2
8XOI	ELECTRON MICROSCOPY	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99527-F1	79.71	0.42

Antibody-complex structures (SAbDab): 5 — 8XOF, 8XOG, 8XOH, 8XOI, 8XOJ

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 1

Disulfide bonds (1): 130–207

Glycosylation sites (3): 25, 32, 44

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-375276	Peptide ligand-binding receptors
R-HSA-418594	G alpha (i) signalling events
R-HSA-9634597	GPER1 signaling

MSigDB gene sets: 475 (showing top): GOBP_POSITIVE_REGULATION_OF_CALCIUM_ION_TRANSPORT, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_CHROMOSOME_ORGANIZATION, GOBP_NEGATIVE_REGULATION_OF_ERK1_AND_ERK2_CASCADE, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_ERBB_SIGNALING_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_SMOOTH_MUSCLE_CELL_PROLIFERATION, GOBP_RESPONSE_TO_ESTRADIOL, GOBP_CORONARY_VASCULATURE_DEVELOPMENT, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CELLULAR_RESPONSE_TO_LIPID

GO Biological Process (58): positive regulation of protein phosphorylation (GO:0001934), positive regulation of neurotransmitter secretion (GO:0001956), negative regulation of leukocyte activation (GO:0002695), inflammatory response (GO:0006954), G protein-coupled receptor signaling pathway (GO:0007186), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), positive regulation of cytosolic calcium ion concentration (GO:0007204), nervous system development (GO:0007399), positive regulation of cell population proliferation (GO:0008284), negative regulation of cell population proliferation (GO:0008285), positive regulation of gene expression (GO:0010628), negative regulation of gene expression (GO:0010629), negative regulation of cell cycle process (GO:0010948), neuronal action potential (GO:0019228), cell differentiation (GO:0030154), apoptotic chromosome condensation (GO:0030263), nuclear fragmentation involved in apoptotic nuclear change (GO:0030264), positive regulation of cell migration (GO:0030335), nuclear receptor-mediated steroid hormone signaling pathway (GO:0030518), positive regulation of insulin secretion (GO:0032024), positive regulation of inositol trisphosphate biosynthetic process (GO:0032962), vasodilation (GO:0042311), positive regulation of apoptotic process (GO:0043065), steroid hormone receptor signaling pathway (GO:0043401), positive regulation of MAPK cascade (GO:0043410), innate immune response (GO:0045087), negative regulation of fat cell differentiation (GO:0045599), positive regulation of epidermal growth factor receptor signaling pathway (GO:0045742), positive regulation of G protein-coupled receptor signaling pathway (GO:0045745), positive regulation of transcription by RNA polymerase II (GO:0045944), negative regulation of inflammatory response (GO:0050728), positive regulation of neurogenesis (GO:0050769), negative regulation of lipid biosynthetic process (GO:0051055), positive regulation of release of sequestered calcium ion into cytosol (GO:0051281), regulation of cytosolic calcium ion concentration (GO:0051480), regulation of cell cycle (GO:0051726), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051898), negative regulation of ERK1 and ERK2 cascade (GO:0070373), positive regulation of ERK1 and ERK2 cascade (GO:0070374)

GO Molecular Function (7): chromatin binding (GO:0003682), G protein-coupled receptor activity (GO:0004930), steroid binding (GO:0005496), nuclear estrogen receptor activity (GO:0030284), G protein-coupled estrogen receptor activity (GO:0038054), steroid hormone binding (GO:1990239), protein binding (GO:0005515)

GO Cellular Component (35): Golgi membrane (GO:0000139), nucleus (GO:0005634), nuclear envelope (GO:0005635), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), early endosome (GO:0005769), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), trans-Golgi network (GO:0005802), cytosol (GO:0005829), plasma membrane (GO:0005886), postsynaptic density (GO:0014069), axon (GO:0030424), dendrite (GO:0030425), cytoplasmic vesicle membrane (GO:0030659), mitochondrial membrane (GO:0031966), dendritic spine membrane (GO:0032591), presynaptic membrane (GO:0042734), dendritic shaft (GO:0043198), axon terminus (GO:0043679), dendritic spine head (GO:0044327), keratin filament (GO:0045095), perinuclear region of cytoplasm (GO:0048471), presynaptic active zone (GO:0048786), recycling endosome (GO:0055037), hippocampal mossy fiber to CA3 synapse (GO:0098686), mitochondrion (GO:0005739), endosome (GO:0005768), cytoskeleton (GO:0005856), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410), cell projection (GO:0042995), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Class A/1 (Rhodopsin-like receptors)	1
GPCR downstream signalling	1
G alpha (s) signalling events	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membrane-bounded organelle	3
endomembrane system	3
cellular anatomical structure	3
cytoplasm	3
G protein-coupled receptor activity	2
cell population proliferation	2
regulation of cell population proliferation	2
gene expression	2
regulation of gene expression	2
apoptotic nuclear changes	2
binding	2
nuclear lumen	2
organelle membrane	2
neuron projection	2
synaptic membrane	2
regulation of protein phosphorylation	1
protein phosphorylation	1
positive regulation of protein modification process	1
positive regulation of phosphorylation	1
neurotransmitter secretion	1
regulation of neurotransmitter secretion	1
positive regulation of synaptic transmission	1
positive regulation of neurotransmitter transport	1
positive regulation of secretion by cell	1
negative regulation of immune system process	1
regulation of leukocyte activation	1
leukocyte activation	1
negative regulation of cell activation	1
defense response	1
signal transduction	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase activator activity	1
regulation of biological quality	1
system development	1
positive regulation of cellular process	1
negative regulation of cellular process	1
positive regulation of macromolecule biosynthetic process	1
negative regulation of macromolecule biosynthetic process	1
regulation of cell cycle process	1
cell cycle process	1

Protein interactions and networks

STRING

1180 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GPER1	ESR2	Q92731	943
GPER1	ESR1	P03372	936
GPER1	GPR62	Q9BZJ7	909
GPER1	GPR61	Q9BZJ8	902
GPER1	EGFR	P00533	841
GPER1	PGR	P06401	716
GPER1	CYP19A1	P11511	713
GPER1	DLG4	P78352	689
GPER1	ESRRG	P62508	656
GPER1	AGT	P01019	621
GPER1	ALB	P02768	604
GPER1	BMP6	P22004	594
GPER1	GNAQ	P50148	588
GPER1	AKT1	P31749	587
GPER1	MAPK3	P27361	573

IntAct

31 interactions, top by confidence:

A	B	Type	Score
GPER1	NHERF1	psi-mi:“MI:0403”(colocalization)	0.610
GPER1	NHERF1	psi-mi:“MI:0915”(physical association)	0.610
NHERF1	GPER1	psi-mi:“MI:0915”(physical association)	0.610
ADRB1	GPER1	psi-mi:“MI:0915”(physical association)	0.570
ADRB1	GPER1	psi-mi:“MI:0403”(colocalization)	0.570
ADRB1	GPER1	psi-mi:“MI:2364”(proximity)	0.570
GPER1	ADRB1	psi-mi:“MI:0914”(association)	0.570
RAMP3	GPER1	psi-mi:“MI:0915”(physical association)	0.540
RAMP3	GPER1	psi-mi:“MI:2364”(proximity)	0.540
FSHR	GPER1	psi-mi:“MI:2364”(proximity)	0.520
GPER1	FSHR	psi-mi:“MI:0403”(colocalization)	0.520
GPER1	FSHR	psi-mi:“MI:2364”(proximity)	0.520
FSHR	GPER1	psi-mi:“MI:0403”(colocalization)	0.520
AKAP5	GPER1	psi-mi:“MI:0915”(physical association)	0.500
GPER1	RAMP1	psi-mi:“MI:0915”(physical association)	0.400
GPER1	RAMP2	psi-mi:“MI:0915”(physical association)	0.400
GPER1	LHCGR	psi-mi:“MI:2364”(proximity)	0.270
	GPER1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (4): GPER1 (Synthetic Growth Defect), GPER1 (Synthetic Growth Defect), GPER1 (Negative Genetic), GPER1 (Affinity Capture-Western)

ESM2 similar proteins: A0T2N3, F7EQ49, O08878, O70526, O88410, O88855, P30411, P46093, P46663, P48146, P49220, P49681, P49682, P49684, P50132, P51680, P51686, P56484, P79960, P97583, Q15722, Q1JQB3, Q1WLP9, Q28642, Q2TAD5, Q3BCU0, Q3T181, Q4KLH9, Q4VA82, Q56UD9, Q5KSK8, Q5MD61, Q61125, Q7SZP9, Q867B2, Q8BMP4, Q8BUD0, Q8HZN9, Q8HZP1, Q8HZP2

Diamond homologs: A0T2N3, A6QNL7, B0F9W3, B3G515, E9QJ73, F1MV99, F7EQ49, O08878, O09047, O19025, O35210, O55197, O70526, O77590, O88680, O97571, P21109, P25023, P25024, P25025, P25095, P25104, P29089, P29754, P29755, P30545, P30555, P30556, P30937, P30938, P31391, P31392, P32303, P34976, P35344, P35351, P35370, P35373, P35374, P35377

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
GPER1	up-regulates	EGFR	binding
tamoxifen	up-regulates	GPER1	“chemical activation”
17beta-estradiol	up-regulates	GPER1	“chemical activation”
GPER1	up-regulates	“1D-myo-inositol 1,4,5-trisphosphate”
GPER1	up-regulates	GNAQ	binding
hsa-miR-424-5p	“down-regulates quantity by repression”	GPER1	“post transcriptional regulation”
GPER1	“up-regulates activity”	hsa-miR-21-5p	“post transcriptional regulation”
GPER1	“up-regulates activity”	GNAS	binding
GPER1	“up-regulates activity”	GNB1	binding
GPER1	“up-regulates activity”	GNG2	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

3 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	3
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

608 predictions. Top by Δscore:

Variant	Effect	Δscore
7:1082273:CGG:C	donor_loss	0.9900
7:1082259:TGG:T	donor_gain	0.9800
7:1082275:G:GG	donor_gain	0.9800
7:1087314:C:CT	donor_gain	0.9600
7:1087315:T:TT	donor_gain	0.9600
7:1091401:CTCCA:C	acceptor_loss	0.9600
7:1091402:TCCA:T	acceptor_loss	0.9600
7:1091403:CCA:C	acceptor_loss	0.9600
7:1091404:CA:C	acceptor_loss	0.9600
7:1082253:TGC:T	donor_gain	0.9500
7:1082261:GAC:G	donor_gain	0.9400
7:1091396:T:A	acceptor_loss	0.9300
7:1091405:A:AG	acceptor_gain	0.9300
7:1091406:G:GG	acceptor_gain	0.9300
7:1082260:G:GA	donor_gain	0.9200
7:1091393:T:A	acceptor_loss	0.8800
7:1091056:A:G	acceptor_gain	0.8700
7:1084339:T:A	donor_gain	0.8500
7:1084329:C:A	donor_gain	0.8400
7:1091931:T:TA	donor_gain	0.8300
7:1091961:T:TA	donor_gain	0.8300
7:1084166:T:TA	donor_gain	0.8100
7:1082277:A:C	donor_loss	0.7900
7:1091396:T:TA	acceptor_gain	0.7700
7:1090543:CCCA:C	donor_gain	0.7600
7:1091850:C:A	donor_gain	0.7600
7:1084170:TGGG:T	donor_gain	0.7400
7:1085250:T:TA	acceptor_gain	0.7400
7:1091894:G:C	donor_gain	0.7400
7:1085246:ATCCT:A	acceptor_gain	0.7300

AlphaMissense

2455 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:1092182:A:C	S152R	0.999
7:1092184:C:A	S152R	0.999
7:1092184:C:G	S152R	0.999
7:1092155:A:C	S143R	0.998
7:1092157:C:A	S143R	0.998
7:1092157:C:G	S143R	0.998
7:1092158:A:C	S144R	0.998
7:1092160:C:A	S144R	0.998
7:1092160:C:G	S144R	0.998
7:1092677:A:C	S317R	0.998
7:1092679:C:A	S317R	0.998
7:1092679:C:G	S317R	0.998
7:1091959:C:A	N77K	0.997
7:1091959:C:G	N77K	0.997
7:1092030:T:C	L101P	0.997
7:1092045:T:C	L106P	0.997
7:1092272:T:A	W182R	0.997
7:1092272:T:C	W182R	0.997
7:1092530:T:C	F268L	0.997
7:1092532:C:A	F268L	0.997
7:1092532:C:G	F268L	0.997
7:1091946:G:A	G73D	0.996
7:1092042:A:C	D105A	0.996
7:1092042:A:G	D105G	0.996
7:1092042:A:T	D105V	0.996
7:1092043:C:A	D105E	0.996
7:1092043:C:G	D105E	0.996
7:1092539:T:C	C271R	0.996
7:1092666:C:A	A313D	0.996
7:1092688:C:A	N320K	0.996

dbSNP variants (sampled 300 via entrez): RS1000090736 (7:1092673 C>T), RS1000988443 (7:1087821 C>T), RS1001248088 (7:1086924 T>G), RS1001630161 (7:1086610 G>A), RS1001830540 (7:1091383 CA>C), RS1002166747 (7:1091506 G>A), RS1002236047 (7:1087732 C>A,G), RS1002565767 (7:1090449 C>G), RS1002609933 (7:1087403 C>T), RS1002983974 (7:1085726 C>T), RS1003204194 (7:1088534 T>G), RS1003315054 (7:1093304 C>G), RS1003803313 (7:1087001 C>CGGGCTTGGG), RS1003830611 (7:1089259 C>G), RS1004373859 (7:1090463 A>C,G)

Disease associations

OMIM: gene MIM:601805 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST011535_2	Prostate cancer	1.000000e-15
GCST90002385_174	High light scatter reticulocyte count	2.000000e-16
GCST90002386_121	High light scatter reticulocyte percentage of red cells	2.000000e-13
GCST90002405_215	Reticulocyte count	4.000000e-18
GCST90002406_234	Reticulocyte fraction of red cells	7.000000e-17

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007986	reticulocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL5169075 (PROTEIN-PROTEIN INTERACTION), CHEMBL5872 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 123,080 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL135	ESTRADIOL	4	123,080

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: gpcr — G protein-coupled estrogen receptor

Most potent curated ligand interactions (9 total), top 9:

Ligand	Action	Affinity	Parameter
[3H]17β-estradiol	Full agonist	8.6	pKd
17β-estradiol	Full agonist	8.5	pKi
G-1	Full agonist	8.0	pKi
2-Methoxyestradiol	Agonist	8.0	pKd
fulvestrant	Full agonist	7.0	pKi
raloxifene	Full agonist	7.0	pKi
G36	Antagonist	6.95	pIC50
G15	Antagonist	6.7	pIC50
tamoxifen	Full agonist	6.0	pKi

Binding affinities (BindingDB)

92 measured of 117 human assays (117 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(E)-3-[3,5-difluoro-4-[(6S,8R)-7-(2-fluoro-2-methylpropyl)-8-methyl-3,6,8,9-tetrahydropyrazolo[4,5-f]isoquinolin-6-yl]phenyl]prop-2-enoic acid	IC50	0.04 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
(E)-3-[3,5-difluoro-4-[(1R,3R)-5-fluoro-2-(2-fluoro-2-methylpropyl)-3-methyl-3,4-dihydro-1H-[1]benzofuro[2,3-c]pyridin-1-yl]phenyl]prop-2-enoic acid	IC50	0.21 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
(E)-3-(3,5-difluoro-4-((1R,3R/1S,3S)-2-(2-fluoro-2-methylpropyl)-3-methyl-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridin-1-yl)phenyl)acrylic acid	IC50	0.21 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
(E)-3-[4-[(1R,3R)-6-(1-ethylpyrazol-4-yl)-2-(2-fluoro-2-methylpropyl)-3-methyl-3,4-dihydro-1H-[1]benzofuro[2,3-c]pyridin-1-yl]-3,5-difluorophenyl]prop-2-enoic acid	IC50	0.24 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
(E)-3-(4-((1S,3R)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-3,5-difluorophenyl)acrylic acid	IC50	0.29 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
(E)-3-[3,5-difluoro-4-[(1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-3,4-dihydro-1H-[1]benzofuro[2,3-c]pyridin-1-yl]phenyl]prop-2-enoic acid	IC50	0.31 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
(E)-3-(3,5-difluoro-4-((1S,3R/1R,3S)-2-(2-fluoro-2-methylpropyl)-3-methyl-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)acrylic acid	IC50	0.32 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
(E)-3-[4-[(1S,3R)-6-(1-ethylpyrazol-4-yl)-2-(2-fluoro-2-methylpropyl)-3-methyl-3,4-dihydro-1H-isoquinolin-1-yl]-3,5-difluorophenyl]prop-2-enoic acid	IC50	0.32 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
(E)-3-[3,5-difluoro-4-[(1S,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-1-yl]phenyl]prop-2-enoic acid	IC50	0.33 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
(E)-3-(3,5-difluoro-4-((1R,3R/1S,3S)-2-(2-fluoro-2-methylpropyl)-3-methyl-6-(pyridin-3-yl)-1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridin-1-yl)phenyl)acrylic acid	IC50	0.36 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
(E)-3-(3,5-difluoro-4-((6S,8R/6R,8S)-(7-isobutyl-8-methyl-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)phenyl)acrylic acid	IC50	0.43 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
(E)-3-(3,5-difluoro-4-((1R,3R/1S,3S)-5-fluoro-2-(2-fluoro-2-methylpropyl)-3-methyl-1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridin-1-yl)phenyl)acrylic acid	IC50	0.45 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
(E)-3-[3,5-difluoro-4-[(1S,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-1-yl]phenyl]prop-2-enoic acid	IC50	0.51 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
(E)-3-(3,5-difluoro-4-((1S,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-6-(2-methylthiazol-5-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)acrylic acid	IC50	0.64 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
(E)-3-(4-((6R,8R/6S,8S)-7-isobutyl-8-methyl-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)phenyl)acrylic acid	IC50	0.64 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
(E)-3-(3,5-difluoro-4-((1S,3R/1R,3S)-2-(2-fluoro-2-methylpropyl)-6-hydroxy-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)acrylic acid	IC50	0.72 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
(E)-3-(3,5-difluoro-4-((1R,3R/1S,3S)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridin-1-yl)phenyl)acrylic acid	IC50	0.73 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
(E)-3-[3,5-difluoro-4-[(5S,7R)-6-(2-fluoro-2-methylpropyl)-7-methyl-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isoquinolin-5-yl]phenyl]prop-2-enoic acid	IC50	0.74 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
(E)-3-(3,5-difluoro-4-((5S,7R/5R,7S)-6-(2-fluoro-2-methylpropyl)-7-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)phenyl)acrylic acid	IC50	0.77 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
(E)-3-(3,5-difluoro-4-((6S,8R/6R,8S)-7-(2-fluoro-2-methylpropyl)-8-methyl-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)phenyl)acrylic acid	IC50	0.77 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
(E)-3-(3,5-difluoro-4-((1S,3R/1R,3S)-2-(2-fluoro-2-methylpropyl)-3-methyl-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)acrylic acid	IC50	0.82 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
(E)-3-(4-((1S,3R/1R,3S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-3,5-difluorophenyl)acrylic acid	IC50	0.84 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
(E)-3-[3,5-difluoro-4-[(1S,3R)-6-isoquinolin-6-yl-3-methyl-2-(2-methylpropyl)-3,4-dihydro-1H-isoquinolin-1-yl]phenyl]prop-2-enoic acid	IC50	0.85 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
(E)-3-(4-((1S,3R/1R,3S)-6-(1-ethyl-1H-pyrazol -4-yl)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-3,5-difluorophenyl)acrylic acid	IC50	0.86 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
(E)-3-(3,5-difluoro-4-((1S,3R/1R,3S)-5-fluoro-2-(2-fluoro-2-methylpropyl)-3-methyl-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)acrylic acid	IC50	0.87 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
(E)-3-[3,5-difluoro-4-[(1S,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-6-quinolin-6-yl-3,4-dihydro-1H-isoquinolin-1-yl]phenyl]prop-2-enoic acid	IC50	1.07 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
(E)-3-(4-((1S,3R/1R,3S)-6-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-2-(2-fluoro-2-methylpropyl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-3,5-difluorophenyl)acrylic acid	IC50	1.17 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
(E)-3-(3,5-difluoro-4-((1R,3R/1S,3S)-2-(2-fluoro-2-methylpropyl)-3-methyl-6-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridin-1-yl)phenyl)acrylic acid	IC50	1.22 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
(E)-3-(3,5-difluoro-4-((1R,3R/1S,3S)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,2,3,4-tetrahydrobenzo[4,5]thieno[2,3-c]pyridin-1-yl)phenyl)acrylic acid	IC50	1.25 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
(E)-3-(3,5-difluoro-4-((1S,3R/1R,3S)-2-(2-fluoro-2-methylpropyl)-3-methyl-6-(2-methylthiazol-5-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)acrylic acid	IC50	1.26 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
(E)-3-(4-((6S,8R/6R,8S)-7-cyclopentyl-8-methyl-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)-3,5-difluorophenyl)acrylic acid	IC50	1.32 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
(E)-3-(3,5-difluoro-4-((1S,3R/1R,3S)-7-fluoro-2-(2-fluoro-2-methylpropyl)-3-methyl-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)acrylic acid	IC50	1.36 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
(E)-3-(4-((1R,3R/1S,3S)-6-(1-ethyl-1H-pyrazol-4-yl)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridin-1-yl)-3,5-difluorophenyl)acrylic acid	IC50	1.39 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
E2-NMe3+	KI	1.4 nM
(E)-3-(3,5-difluoro-4-((1S,3R/1R,3S)-2-(2-fluoro-2-methylpropyl)-3-methyl-6-(2-(methylamino)-2-oxoethoxy)-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)acrylic acid	IC50	1.45 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
(E)-3-(4-((1S,3R/1R,3S)-6-(1-ethyl-1H-pyrazol-4-yl)-5-fluoro-2-(2-fluoro-2-methylpropyl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-3,5-difluorophenyl)acrylic acid	IC50	1.5 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
(E)-3-(3,5-difluoro-4-((1S,3R/1R,3S)-2-(2-fluoro-2-methylpropyl)-3-methyl-6-(1-propyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)acrylic acid	IC50	1.52 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
(E)-3-(3,5-difluoro-4-((1S,3R/1R,3S)-2-(2-fluoro-2-methylpropyl)-3-methyl-6-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)acrylic acid	IC50	1.59 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
(1S,10R,11S,14S,15S)-15-methyltetracyclo[8.7.0.0^{2,7}.0^{11,15}]heptadeca-2,4,6-triene-5,14-diol	IC50	1.7 nM	US-9422324: 6-substituted demethyl-estradiol derivatives as selective ER-β agonists
(E)-3-(3,5-difluoro-4-((1S,3R/1R,3S)-2-(2-fluoro-2-methylpropyl)-3-methyl-6-(quinolin-6-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)acrylic acid	IC50	1.7 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
(E)-3-(3,5-difluoro-4-((1S,3R/1R,3S)-2-(2-fluoro-2-methylpropyl)-6-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)acrylic acid	IC50	1.82 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
(E)-3-[3,5-difluoro-4-[(1S,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-6-[2-(1-methylpyrazol-4-yl)ethynyl]-3,4-dihydro-1H-isoquinolin-1-yl]phenyl]prop-2-enoic acid	IC50	1.85 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
(E)-3-(3,5-difluoro-4-((5S,7R/5R,7S)-6-(2-fluoro-2-methylpropyl)-7-methyl-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-5-yl)phenyl)acrylic acid	IC50	1.88 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
(E)-3-(3,5-difluoro-4-((1S,3R/1R,3S)-2-(2-fluoro-2-methylpropyl)-3-methyl-6-morpholino-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)acrylic acid	IC50	1.94 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
E2-COO-	KI	2 nM
(E)-3-(4-((1S,3R/1R,3S)-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-3,5-difluorophenyl)acrylic acid	IC50	2.11 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
(E)-3-(3,5-difluoro-4-((1S,3R/1R,3 S)-2-(2-fluoro-2-methylpropyl)-3-methyl-6-(pyridin-3-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)acrylic acid	IC50	2.28 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
(E)-3-(3,5-difluoro-4-((6S,8R/6R,8S)-7-(2-fluoro-2-methylpropyl)-8-methyl-2-oxo-6,7,8,9-tetrahydro-2H-pyrano[2,3-g]isoquinolin-6-yl)phenyl)acrylic acid	IC50	2.47 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof
E2-NB	KI	2.7 nM
(E)-3-(3,5-difluoro-4-((1R,3R/1S,3S)-8-fluoro-2-(2-fluoro-2-methylpropyl)-3-methyl-1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridin-1-yl)phenyl)acrylic acid	IC50	2.97 nM	US-10087191: Piperidine derivative and preparation method and pharmaceutical use thereof

ChEMBL bioactivities

109 potent at pChembl≥5 of 109 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.40	IC50	0.04	nM	CHEMBL4448852
9.68	IC50	0.21	nM	CHEMBL5979005
9.68	IC50	0.21	nM	CHEMBL5964875
9.62	IC50	0.24	nM	CHEMBL5835059
9.54	IC50	0.29	nM	CHEMBL5841693
9.52	EC50	0.3	nM	ESTRADIOL
9.51	IC50	0.31	nM	CHEMBL5904942
9.49	IC50	0.32	nM	CHEMBL5740053
9.49	IC50	0.32	nM	CHEMBL5827662
9.48	IC50	0.33	nM	CHEMBL5920005
9.44	IC50	0.36	nM	CHEMBL6004991
9.37	IC50	0.43	nM	CHEMBL5967118
9.35	IC50	0.45	nM	CHEMBL5761732
9.29	IC50	0.51	nM	CHEMBL5951465
9.19	IC50	0.64	nM	CHEMBL5833057
9.19	IC50	0.64	nM	CHEMBL6032703
9.14	IC50	0.72	nM	CHEMBL5927812
9.14	IC50	0.73	nM	CHEMBL5924129
9.13	IC50	0.74	nM	CHEMBL5938490
9.11	IC50	0.77	nM	CHEMBL5766406
9.11	IC50	0.77	nM	CHEMBL5915577
9.09	IC50	0.82	nM	CHEMBL6005597
9.08	IC50	0.84	nM	CHEMBL5983785
9.07	IC50	0.86	nM	CHEMBL5825226
9.07	IC50	0.85	nM	CHEMBL6065669
9.06	IC50	0.87	nM	CHEMBL6061420
8.97	IC50	1.07	nM	CHEMBL5974785
8.93	IC50	1.17	nM	CHEMBL5819525
8.91	IC50	1.22	nM	CHEMBL5886900
8.90	IC50	1.25	nM	CHEMBL5955907
8.90	IC50	1.26	nM	CHEMBL5945249
8.88	IC50	1.32	nM	CHEMBL5839289
8.87	IC50	1.36	nM	CHEMBL5843070
8.86	IC50	1.39	nM	CHEMBL6034275
8.84	IC50	1.45	nM	CHEMBL5791507
8.82	IC50	1.52	nM	CHEMBL5957467
8.82	IC50	1.5	nM	CHEMBL6034914
8.80	IC50	1.59	nM	CHEMBL5926577
8.77	IC50	1.7	nM	CHEMBL5792993
8.74	IC50	1.82	nM	CHEMBL5754044
8.73	IC50	1.85	nM	CHEMBL5894718
8.73	IC50	1.88	nM	CHEMBL5999411
8.71	IC50	1.94	nM	CHEMBL6045088
8.70	EC50	2	nM	CHEMBL569766
8.68	IC50	2.11	nM	CHEMBL5897592
8.64	IC50	2.28	nM	CHEMBL6008545
8.61	IC50	2.47	nM	CHEMBL5778911
8.57	Ki	2.7	nM	ESTRADIOL
8.53	IC50	2.97	nM	CHEMBL5900040
8.50	IC50	3.14	nM	CHEMBL5843499

PubChem BioAssay actives

26 with measured affinity, of 117 total; 12 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
Estradiol	503076: Agonist activity at GFP-tagged GPR30 expressed in COS7 cells assessed as half life for increase in intracellular calcium level by spectrofluorimetry	ec50	0.0003	uM
1-[(3aS,4R,9bR)-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl]ethanone	503076: Agonist activity at GFP-tagged GPR30 expressed in COS7 cells assessed as half life for increase in intracellular calcium level by spectrofluorimetry	ec50	0.0020	uM
1-[(3aS,9bR)-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl]ethanone	1855808: Agonist activity at GPER (unknown origin)	ki	0.0110	uM
tert-butyl N-[[4-[2-[(13S,17S)-3,17-dihydroxy-13-methyl-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthren-17-yl]ethynyl]phenyl]methyl]carbamate	1799418: Competitive Binding Assay from Article 10.1021/cb700072n: “Synthetic estrogen derivatives demonstrate the functionality of intracellular GPR30.”	ki	0.0160	uM
[4-[2-[(13S,17S)-3,17-dihydroxy-13-methyl-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthren-17-yl]ethynyl]phenyl]-trimethylazanium	1799418: Competitive Binding Assay from Article 10.1021/cb700072n: “Synthetic estrogen derivatives demonstrate the functionality of intracellular GPR30.”	ki	0.0170	uM
5-fluoro-N-[5-[(4-fluorophenyl)methyl]-1,3-thiazol-2-yl]-1H-indole-2-carboxamide	1387592: Agonist activity at GPER (unknown origin) expressed in human HL60 cells assessed as increase in cAMP accumulation in presence of IBMX after 15 mins by HTRF assay	ec50	0.0200	uM
(3aS,4R,9bR)-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline	443558: Binding affinity to GPR30	ic50	0.0200	uM
3-chloro-6-fluoro-N-(5-hydroxy-3,4,6-trimethyl-2-pyridinyl)-1-benzothiophene-2-carboxamide	2085075: Binding affinity to human GPER by SPR method	kd	0.0237	uM
[4-[2-[(13S,17S)-3,17-dihydroxy-13-methyl-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthren-17-yl]ethynyl]phenyl]methylazanium	1799418: Competitive Binding Assay from Article 10.1021/cb700072n: “Synthetic estrogen derivatives demonstrate the functionality of intracellular GPR30.”	ki	0.0250	uM
3-[2-[(13S,17S)-3,17-dihydroxy-13-methyl-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthren-17-yl]ethynyl]benzoate	1799418: Competitive Binding Assay from Article 10.1021/cb700072n: “Synthetic estrogen derivatives demonstrate the functionality of intracellular GPR30.”	ki	0.0300	uM
5-bromo-3-chloro-N-(4-ethyl-5-methyl-1,3-thiazol-2-yl)-1H-indole-2-carboxamide	1387592: Agonist activity at GPER (unknown origin) expressed in human HL60 cells assessed as increase in cAMP accumulation in presence of IBMX after 15 mins by HTRF assay	ec50	0.4800	uM
3-chloro-N-[5-[(2,4-difluorophenyl)methyl]-1,3-thiazol-2-yl]-1H-indole-2-carboxamide	1387592: Agonist activity at GPER (unknown origin) expressed in human HL60 cells assessed as increase in cAMP accumulation in presence of IBMX after 15 mins by HTRF assay	ec50	1.6200	uM

CTD chemical–gene interactions

109 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Estradiol	increases activity, decreases expression, increases cleavage, affects response to substance, affects cotreatment (+8 more)	25
bisphenol A	decreases expression, decreases reaction, increases phosphorylation, increases reaction, increases response to substance (+5 more)	20
Fulvestrant	decreases expression, decreases response to substance, affects reaction, increases activity, increases reaction (+6 more)	9
4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-3H-cyclopenta(c)quinoline	decreases reaction, increases expression, affects binding, decreases activity, affects cotreatment	8
1-(4-(6-bromobenzo(1,3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta(c)quinolin-8-yl)ethanone	increases phosphorylation, increases reaction, increases activity, increases expression, decreases reaction (+2 more)	6
Tamoxifen	affects localization, increases reaction, increases activity, decreases reaction, affects reaction (+4 more)	6
Cadmium	increases phosphorylation, increases secretion, increases expression, decreases expression, decreases reaction (+4 more)	5
bisphenol AF	increases expression, affects reaction, increases phosphorylation, affects binding	4
Quercetin	affects reaction, increases expression, decreases expression, decreases reaction	4
Cadmium Chloride	increases expression, affects reaction, increases activity, increases phosphorylation, decreases expression (+1 more)	4
tetrachlorodian	decreases reaction, increases expression, affects binding	3
bisphenol B	decreases expression, affects binding	3
Acetaminophen	decreases expression, increases expression	3
Tetrachlorodibenzodioxin	increases expression	3
Cyclosporine	decreases expression, increases expression	3
Genistein	decreases expression, decreases reaction, affects reaction, increases expression, affects binding (+1 more)	3
Raloxifene Hydrochloride	increases expression, affects localization, affects reaction, decreases expression	3
bisphenol F	decreases expression, affects binding	2
naringenin	decreases expression, affects cotreatment	2
methylparaben	increases expression	2
afimoxifene	increases cleavage, increases expression, affects response to substance, increases activity, affects reaction	2
sodium arsenite	affects expression, increases expression	2
butylparaben	increases expression	2
2,2’,4,4’-tetrabromodiphenyl ether	decreases reaction, decreases expression, affects binding	2
bisphenol S	affects binding, decreases expression	2
Arsenic Trioxide	decreases expression	2
Atrazine	affects expression, affects binding, increases activity, decreases reaction, increases expression (+2 more)	2
Silicon Dioxide	increases expression, decreases expression	2
Zearalenone	affects binding, decreases expression	2
aristolochic acid I	increases expression	1

ChEMBL screening assays

43 unique, capped per target: 24 functional, 19 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5217359	Binding	PROTAC activity at VHL/GPER (unknown origin) assessed as degradation of GPER	Natural Product-Inspired Targeted Protein Degraders: Advances and Perspectives. — J Med Chem
CHEMBL1049720	Functional	Agonist activity at GPR30 in human SKBr3 cells assessed as stimulation of calcium mobilization at 10 uM relative to 200 nM estradiol	Synthesis and characterization of iodinated tetrahydroquinolines targeting the G protein-coupled estrogen receptor GPR30. — J Med Chem

Cellosaurus cell lines

4 cell lines: 3 cancer cell line, 1 spontaneously immortalized cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B8GZ	Abcam HCT 116 GPER1 KO	Cancer cell line	Male
CVCL_B9J8	Abcam A-549 GPER1 KO	Cancer cell line	Male
CVCL_D2FF	Abcam MCF-7 GPER1 KO	Cancer cell line	Female
CVCL_KX56	PathHunter CHO-K1 GPR30 beta-arrestin	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.