GRK3

Summary

GRK3 (G protein-coupled receptor kinase 3, HGNC:290) is a protein-coding gene on chromosome 22q12.1, encoding G protein-coupled receptor kinase 3 (P35626). receptors.

The beta-adrenergic receptor kinase specifically phosphorylates the agonist-occupied form of the beta-adrenergic and related G protein-coupled receptors. Overall, the beta adrenergic receptor kinase 2 has 85% amino acid similarity with beta adrenergic receptor kinase 1, with the protein kinase catalytic domain having 95% similarity. These data suggest the existence of a family of receptor kinases which may serve broadly to regulate receptor function.

Source: NCBI Gene 157 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 31 total
• Druggable target: yes
• MANE Select transcript: NM_005160

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:290
Approved symbol	GRK3
Name	G protein-coupled receptor kinase 3
Location	22q12.1
Locus type	gene with protein product
Status	Approved
Aliases	BARK2
Ensembl gene	ENSG00000100077
Ensembl biotype	protein_coding
OMIM	109636
Entrez	157

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 6 protein_coding, 1 nonsense_mediated_decay

ENST00000324198, ENST00000455558, ENST00000869559, ENST00000928045, ENST00000947204, ENST00000947205, ENST00000947206

RefSeq mRNA: 2 — MANE Select: NM_005160 NM_001362778, NM_005160

CCDS: CCDS13832

Canonical transcript exons

ENST00000324198 — 21 exons

Exon	Start	End
ENSE00000651787	25564675	25565153
ENSE00000651788	25604377	25604453
ENSE00000651789	25644592	25644665
ENSE00000651802	25687537	25687667
ENSE00000651803	25690189	25690283
ENSE00000651804	25695107	25695214
ENSE00000651805	25703510	25703576
ENSE00000651806	25704109	25704209
ENSE00000651807	25709898	25709964
ENSE00000651809	25714408	25714570
ENSE00000651810	25718245	25718381
ENSE00000651811	25721284	25721397
ENSE00001265880	25711068	25711163
ENSE00001265950	25722289	25729294
ENSE00001744050	25685170	25685248
ENSE00003462779	25674437	25674528
ENSE00003512265	25667739	25667800
ENSE00003581699	25678816	25678915
ENSE00003650766	25661576	25661677
ENSE00003658611	25663630	25663704
ENSE00003677641	25672296	25672347

Expression profiles

Bgee: expression breadth ubiquitous, 260 present calls, max score 98.26.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.2288 / max 223.9980, expressed in 1249 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
191474	3.8971	941
191476	3.5703	965
191475	1.6776	431
191477	1.0838	410

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
Brodmann (1909) area 23	UBERON:0013554	98.26	gold quality
middle temporal gyrus	UBERON:0002771	97.71	gold quality
endothelial cell	CL:0000115	94.03	gold quality
substantia nigra pars compacta	UBERON:0001965	93.36	gold quality
parietal pleura	UBERON:0002400	92.70	gold quality
monocyte	CL:0000576	92.65	gold quality
parietal lobe	UBERON:0001872	92.56	gold quality
postcentral gyrus	UBERON:0002581	92.34	gold quality
entorhinal cortex	UBERON:0002728	92.18	gold quality
mononuclear cell	CL:0000842	91.96	gold quality
leukocyte	CL:0000738	91.63	gold quality
sperm	CL:0000019	91.60	gold quality
lateral nuclear group of thalamus	UBERON:0002736	91.38	gold quality
substantia nigra pars reticulata	UBERON:0001966	91.20	gold quality
superior frontal gyrus	UBERON:0002661	91.07	gold quality
pleura	UBERON:0000977	90.80	gold quality
visceral pleura	UBERON:0002401	90.69	gold quality
primary visual cortex	UBERON:0002436	89.87	gold quality
occipital lobe	UBERON:0002021	89.19	gold quality
male germ cell	CL:0000015	88.64	gold quality
superior vestibular nucleus	UBERON:0007227	87.24	gold quality
cortical plate	UBERON:0005343	87.09	gold quality
pons	UBERON:0000988	86.80	gold quality
islet of Langerhans	UBERON:0000006	85.88	gold quality
adipose tissue	UBERON:0001013	85.38	gold quality
lateral globus pallidus	UBERON:0002476	85.35	gold quality
granulocyte	CL:0000094	85.05	gold quality
connective tissue	UBERON:0002384	84.87	gold quality
skin of hip	UBERON:0001554	84.79	gold quality
thoracic mammary gland	UBERON:0005200	84.32	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	14.53
E-MTAB-6379	no	960.24

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR

miRNA regulators (miRDB)

266 targeting GRK3, 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-8485	100.00	77.57	4731
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-551B-5P	99.96	71.28	3493

Literature-anchored findings (GeneRIF, showing 23)

• dysregulation in GRK3 expression alters signaling desensitization, and thereby predisposes to the development of bipolar disorder (PMID:12808434)
• the CRH-R1alpha carboxyl tail is important for regulation of receptor activity by G protein-coupled receptor kinase (PMID:15498832)
• ATP stimulation leads to GRK3 phosphorylation of P2X(7) receptor. (PMID:15728711)
• No support for a major role for GRK3 gene promoter variants in cocaine addiction. (PMID:17621168)
• Dysregulation in GRK3 expression alters signaling desensitization and thereby predisposes to the development of bipolar disease. (PMID:18075471)
• role for GRK3 in regulating CXCR4 attenuation and have provided a mechanistic link between the GRK3 pathway and the CXCR4-related WHIM(WT) disorder. (PMID:18274673)
• The G-384A variant may alter binding of Sp1/Sp4 transcription factors resulting in an increase in gene transcription and an increase in vulnerability to bipolar disorder. (PMID:18359007)
• we found no evidence of altered levels of acetylated histone H3 at the affected allele compared to the common allele (PMID:19766236)
• mRNA levels for GRK3 were inversely correlated with systolic and diastolic blood pressure (day, night and 24 h), which suggests a protective role for GRK3 in the regulation of human blood pressure (PMID:20216086)
• A reduced cortical concentration of GRK3 in schizophrenia (resembling that in aging) may result in altered G protein-dependent signaling, thus contributing to prefrontal deficits in schizophrenia. (PMID:21784156)
• In oral squamous cell carcinomas, malignant cells and surrounding tissue overexpress the ADRBK2 gene. (PMID:21916780)
• GRK3 is a negative regulator of cell growth whose expression is preferentially reduced in glioblastoma of the classical subtype as a consequence of activity in primary gliomagenic pathways. (PMID:22086906)
• Data indicate that CXCL12-induced phosphorylation at CXCR4 S346/347 was mediated by GRK2/3. (PMID:23734232)
• data are consistent with the possibility that oncogenes can induce cellular stiffness via an HDAC6-induced reorganization of the vimentin intermediate filament network (PMID:24434559)
• effects of GRK3 modulation appear to be specific to chemokine-mediated migration behaviors without influencing tumor cell proliferation or survival (PMID:27049755)
• GRK3 is a new critical activator of neuroendocrine phenotypes and mediator of CREB activation in promoting neuroendocrine differentiation of prostate cancer cells. (PMID:27191986)
• hat expression of GRK3 was down-regulated in pancreatic ductal adenocarcinoma and was an independent prognostic factor (PMID:29254792)
• Study found that GRK3 was significantly overexpressed in 162 pairs of colon cancer tissues than in the matched noncancerous mucosa. These data show that aberrant expression of GRK3 plays an important role in promoting colon cancer progression through enhanced proliferation and reduced apoptosis. (PMID:29445249)
• RKIP has several binding sites within the N-termini of GRK3.The N-termini of GRK3 binds to beta2-adrenoceptors. (PMID:31604529)
• Dissecting the roles of GRK2 and GRK3 in mu-opioid receptor internalization and beta-arrestin2 recruitment using CRISPR/Cas9-edited HEK293 cells. (PMID:33060647)
• TEAD3 inhibits the proliferation and metastasis of prostate cancer via suppressing ADRBK2. (PMID:36907139)
• Aged G Protein-Coupled Receptor Kinase 3 (Grk3)-Deficient Mice Exhibit Enhanced Osteoclastogenesis and Develop Bone Lesions Analogous to Human Paget’s Disease of Bone. (PMID:37048054)
• A novel GRK3-HDAC2 regulatory pathway is a key direct link between neuroendocrine differentiation and angiogenesis in prostate cancer progression. (PMID:37543278)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	grk3	ENSDARG00000104094
mus_musculus	Grk3	ENSMUSG00000042249
rattus_norvegicus	Grk3	ENSRNOG00000059456

Paralogs (7): GRK7 (ENSG00000114124), GRK4 (ENSG00000125388), RSKR (ENSG00000167524), GRK2 (ENSG00000173020), GRK1 (ENSG00000185974), GRK6 (ENSG00000198055), GRK5 (ENSG00000198873)

Protein

Protein identifiers

G protein-coupled receptor kinase 3 — P35626 (reviewed: P35626)

Alternative names: Beta-adrenergic receptor kinase 2

All UniProt accessions (2): P35626, H7C099

UniProt curated annotations — full annotation on UniProt →

Function. receptors. Also phosphorylates ligand-bound C3a and C5a anaphylatoxin receptors (C3AR1 and C5AR1, respectively), leading to receptor desensitization.

Subunit / interactions. Interacts with GIT1.

Subcellular location. Postsynapse. Presynapse.

Post-translational modifications. Ubiquitinated.

Similarity. Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. GPRK subfamily.

RefSeq proteins (2): NP_001349707, NP_005151* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000239	GPCR_kinase	Family
IPR000719	Prot_kinase_dom	Domain
IPR000961	AGC-kinase_C	Domain
IPR001849	PH_domain	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR016137	RGS	Domain
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR036305	RGS_sf	Homologous_superfamily
IPR044926	RGS_subdomain_2	Homologous_superfamily

Pfam: PF00069, PF00169, PF00615

Enzyme classification (BRENDA):

• EC 2.7.11.15 — beta-adrenergic-receptor kinase (BRENDA: 10 organisms, 296 substrates, 190 inhibitors, 32 Km, 3 kcat entries)

Substrate kinetics (BRENDA)

13 substrates with measured Km, best-characterized 13. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.017–0.149	6
RHODOPSIN	0.0038–0.014	4
DEMEFTEAESNMN	0.0339	3
DEMEFTEAESNMNDLVSEYQ	0.0324	2
GEGMDEMEFTEAESNMN	0.1	2
RRREEEEESAAA	0.72–1.34	2
BETA-ADRENERGIC RECEPTOR	0.0003	1
EEMEFSEAEANMN	0.054	1
RRRAEASAA	5.1	1
RRRASAAASAA	3.3	1
RRRASASAA	5.4	1
RRRASPAAASAA	4.6	1
RRRASPASAA	3.4	1

Catalyzed reactions (Rhea), 1 shown:

• [beta-adrenergic receptor] + ATP = [beta-adrenergic receptor]-phosphate + ADP + H(+) (RHEA:19429)

UniProt features (15 total): domain 4, sequence variant 4, region of interest 2, binding site 2, chain 1, sequence conflict 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P35626-F1	89.78	0.74

Functional residue map

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

Catalytic / active sites (1): 317 (proton acceptor)

Ligand- & substrate-binding residues (2): 197–205; 220

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-418555	G alpha (s) signalling events
R-HSA-8856825	Cargo recognition for clathrin-mediated endocytosis
R-HSA-162582	Signal Transduction
R-HSA-199991	Membrane Trafficking
R-HSA-372790	Signaling by GPCR
R-HSA-388396	GPCR downstream signalling
R-HSA-5653656	Vesicle-mediated transport
R-HSA-8856828	Clathrin-mediated endocytosis

MSigDB gene sets: 228 (showing top): BENPORATH_ES_WITH_H3K27ME3, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, HASLINGER_B_CLL_WITH_11Q23_DELETION, RUTELLA_RESPONSE_TO_CSF2RB_AND_IL4_UP, FOSTER_TOLERANT_MACROPHAGE_UP, RUTELLA_RESPONSE_TO_HGF_VS_CSF2RB_AND_IL4_DN, GOBP_RECEPTOR_INTERNALIZATION, KEGG_OLFACTORY_TRANSDUCTION, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_UP, GOMF_G_PROTEIN_COUPLED_RECEPTOR_BINDING, KEGG_ENDOCYTOSIS, LEE_AGING_CEREBELLUM_DN, GOMF_SIGNALING_RECEPTOR_BINDING, GOBP_IMPORT_INTO_CELL

GO Biological Process (5): desensitization of G protein-coupled receptor signaling pathway (GO:0002029), signal transduction (GO:0007165), G protein-coupled receptor signaling pathway (GO:0007186), receptor internalization (GO:0031623), protein phosphorylation (GO:0006468)

GO Molecular Function (10): G protein-coupled receptor binding (GO:0001664), protein kinase activity (GO:0004672), G protein-coupled receptor kinase activity (GO:0004703), ATP binding (GO:0005524), beta-adrenergic receptor kinase activity (GO:0047696), nucleotide binding (GO:0000166), protein serine/threonine kinase activity (GO:0004674), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (7): cytosol (GO:0005829), plasma membrane (GO:0005886), presynapse (GO:0098793), postsynapse (GO:0098794), cytoplasm (GO:0005737), cell projection (GO:0042995), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
GPCR downstream signalling	1
Clathrin-mediated endocytosis	1
Vesicle-mediated transport	1
Signal Transduction	1
Signaling by GPCR	1
Membrane Trafficking	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
protein kinase activity	2
synapse	2
negative adaptation of signaling pathway	1
negative regulation of G protein-coupled receptor signaling pathway	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
G protein-coupled receptor activity	1
signal transduction	1
receptor-mediated endocytosis	1
phosphorylation	1
protein modification process	1
signaling receptor binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
protein serine/threonine kinase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
cytoplasm	1
membrane	1
cell periphery	1
intracellular anatomical structure	1
cell junction	1

Protein interactions and networks

STRING

1680 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GRK3	SAG	P10523	884
GRK3	ARRB2	P32121	829
GRK3	MYO18B	Q8IUG5	819
GRK3	SEZ6L	Q9BYH1	816
GRK3	GNB2	P11016	700
GRK3	SUCLG2	Q96I99	665
GRK3	ARRB1	P49407	657
GRK3	RHO	P08100	591
GRK3	HSP90AB1	P08238	578
GRK3	HSP90AA1	P07900	575
GRK3	IFNAR2	P48551	544
GRK3	ADRB2	P07550	514
GRK3	RACK1	P25388	491
GRK3	CXCR4	P30991	483
GRK3	CXCL12	P48061	478

IntAct

10 interactions, top by confidence:

A	B	Type	Score
GRK2	GRK3	psi-mi:“MI:0915”(physical association)	0.690
GRK3	H1-5	psi-mi:“MI:0915”(physical association)	0.400
Opn4	GRK2	psi-mi:“MI:0915”(physical association)	0.400
HSPB1	GRK3	psi-mi:“MI:0915”(physical association)	0.370
TEX101	MAP4K4	psi-mi:“MI:0914”(association)	0.350
GRK2	HSP90AA1	psi-mi:“MI:0914”(association)	0.350
	ESYT2	psi-mi:“MI:0914”(association)	0.350
groEL	GRK3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (20): ADRBK2 (Two-hybrid), ADRBK2 (Affinity Capture-MS), ADRBK2 (Biochemical Activity), ADRBK2 (Affinity Capture-MS), ADRBK2 (Reconstituted Complex), ADRBK2 (Affinity Capture-RNA), ADRBK2 (Affinity Capture-MS), ADRBK2 (Affinity Capture-Western), ADRBK2 (Proximity Label-MS), CXCR4 (Affinity Capture-Western), ADRBK2 (Affinity Capture-Western), ADRBK2 (Affinity Capture-MS), ADRBK2 (Affinity Capture-MS), ADRBK2 (Proximity Label-MS), ADRBK2 (Affinity Capture-MS)

ESM2 similar proteins: A1Z9X0, A8WUG4, A8XWC4, F1M7Y5, O13310, O19111, O74536, O97627, P00518, P07934, P09217, P13286, P23443, P26817, P26818, P26819, P31325, P34722, P35626, P41743, P54645, P54646, P67998, P67999, P83099, Q02111, Q02956, Q04759, Q05513, Q09137, Q12706, Q13131, Q16816, Q19266, Q21734, Q28948, Q2KJ16, Q3UYH7, Q5EG47, Q5R4K9

Diamond homologs: A1A4I4, A1Z7T0, A7MBL8, B6CZ17, B6CZ18, J9W0G9, O08874, O19111, O70291, O70293, O97627, P04409, P05130, P05696, P09215, P09217, P10102, P10830, P12688, P13678, P16054, P17252, P18961, P21146, P23298, P24723, P25098, P26817, P26818, P26819, P28327, P28867, P31748, P31749, P31750, P31751, P32298, P32865, P32866, P34102

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
GRK3	“down-regulates activity”	BDKRB2	phosphorylation
GRK3	“down-regulates activity”	TBXA2R	phosphorylation
GRK3	“down-regulates activity”	C3AR1	phosphorylation
GRK3	“down-regulates activity”	OPRM1	phosphorylation
GRK3	“down-regulates activity”	CCR5	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	5
Likely benign	6
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

3909 predictions. Top by Δscore:

Variant	Effect	Δscore
22:25565149:CCCAG:C	donor_loss	1.0000
22:25565150:CCAG:C	donor_loss	1.0000
22:25565151:CAGG:C	donor_loss	1.0000
22:25565152:AGGT:A	donor_loss	1.0000
22:25565153:GGTAC:G	donor_loss	1.0000
22:25565154:G:GA	donor_loss	1.0000
22:25565155:T:G	donor_loss	1.0000
22:25604375:A:AG	acceptor_gain	1.0000
22:25604376:G:GT	acceptor_gain	1.0000
22:25604376:GT:G	acceptor_gain	1.0000
22:25661574:A:AG	acceptor_gain	1.0000
22:25661575:G:GG	acceptor_gain	1.0000
22:25661678:G:GG	donor_gain	1.0000
22:25663628:A:AG	acceptor_gain	1.0000
22:25663629:G:GG	acceptor_gain	1.0000
22:25672294:A:AG	acceptor_gain	1.0000
22:25672295:G:GA	acceptor_gain	1.0000
22:25672343:TCCAT:T	donor_gain	1.0000
22:25672348:G:GG	donor_gain	1.0000
22:25674425:T:A	acceptor_gain	1.0000
22:25674426:G:A	acceptor_gain	1.0000
22:25674435:A:AG	acceptor_gain	1.0000
22:25674436:G:GA	acceptor_gain	1.0000
22:25674436:GTT:G	acceptor_gain	1.0000
22:25674529:G:GG	donor_gain	1.0000
22:25678911:CAGGA:C	donor_gain	1.0000
22:25678913:GGA:G	donor_gain	1.0000
22:25678914:GA:G	donor_gain	1.0000
22:25678914:GAG:G	donor_gain	1.0000
22:25678916:G:GG	donor_gain	1.0000

AlphaMissense

4607 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:25565068:G:C	D10H	1.000
22:25565069:A:T	D10V	1.000
22:25565081:T:C	L14P	1.000
22:25672321:T:A	W177R	1.000
22:25672321:T:C	W177R	1.000
22:25674453:T:C	F191S	1.000
22:25674465:G:C	R195T	1.000
22:25674465:G:T	R195M	1.000
22:25674466:G:C	R195S	1.000
22:25674466:G:T	R195S	1.000
22:25674471:T:A	I197N	1.000
22:25674473:G:A	G198R	1.000
22:25674473:G:C	G198R	1.000
22:25674474:G:A	G198E	1.000
22:25674474:G:T	G198V	1.000
22:25674479:G:A	G200R	1.000
22:25674479:G:C	G200R	1.000
22:25674480:G:A	G200E	1.000
22:25674480:G:T	G200V	1.000
22:25674483:G:A	G201E	1.000
22:25674485:T:A	F202I	1.000
22:25674485:T:C	F202L	1.000
22:25674485:T:G	F202V	1.000
22:25674486:T:C	F202S	1.000
22:25674486:T:G	F202C	1.000
22:25674487:C:A	F202L	1.000
22:25674487:C:G	F202L	1.000
22:25674488:G:A	G203R	1.000
22:25674488:G:C	G203R	1.000
22:25674488:G:T	G203W	1.000

dbSNP variants (sampled 300 via entrez): RS1000023671 (22:25574438 G>A), RS1000039138 (22:25686852 C>T), RS1000063056 (22:25614841 A>G), RS1000100020 (22:25700567 T>A,C), RS1000123560 (22:25572303 T>C), RS1000135484 (22:25728562 C>T), RS1000159503 (22:25659639 G>A), RS1000162505 (22:25637186 T>C), RS1000195146 (22:25724120 A>T), RS1000204037 (22:25642585 A>C), RS1000211050 (22:25591286 G>A,C), RS1000215657 (22:25719517 C>G), RS1000265953 (22:25686037 C>G,T), RS1000268089 (22:25617886 C>A,T), RS1000274132 (22:25683838 A>G,T)

Disease associations

OMIM: gene MIM:109636 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006281_17	Coronary artery disease in type 1 diabetes	9.000000e-06
GCST007675_5	3-month functional outcome in non-lacunar ischaemic stroke (modified Rankin score)	2.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009603	stroke outcome severity measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1075166 (SINGLE PROTEIN)

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs5761122	GRK3		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Beta-adrenergic receptor kinases (βARKs)

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
compound 101 [PMID: 21596927]	Inhibition	7.49	pIC50
balanol	Inhibition	7.33	pIC50

Binding affinities (BindingDB)

8 measured of 8 human assays (8 total across all organisms); most potent 8 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(2S)-1-[1-(2-methoxyphenyl)propan-2-ylamino]-3-[(3-methyl-2,3,3a,4,5,6,7,7a-octahydro-1H-indazol-4-yl)oxy]propan-2-ol	IC50	0.009 nM	US-11173144: Adrenergic receptor modulating compounds and methods of using the same
(2S)-1-[(1-methoxy-2-methylpropan-2-yl)amino]-3-[(3-methyl-2H-indazol-4-yl)oxy]propan-2-ol	IC50	0.019 nM	US-11173144: Adrenergic receptor modulating compounds and methods of using the same
(2S)-1-[2-(2-methoxyphenoxy)ethylamino]-3-[(3-methyl-2,3,3a,4,5,6,7,7a-octahydro-1H-indazol-4-yl)oxy]propan-2-ol	IC50	0.024 nM	US-11173144: Adrenergic receptor modulating compounds and methods of using the same
(2S)-1-[(3-methyl-2,3,3a,4,5,6,7,7a-octahydro-1H-indazol-4-yl)oxy]-3-[2-[2-(trifluoromethyl)phenyl]ethylamino]propan-2-ol	IC50	0.048 nM	US-11173144: Adrenergic receptor modulating compounds and methods of using the same
(2S)-1-(tert-butylamino)-3-[(3-methyl-2H-indazol-4-yl)oxy]propan-2-ol	IC50	0.065 nM	US-11173144: Adrenergic receptor modulating compounds and methods of using the same
(2S)-1-[(3-methyl-2,3,3a,4,5,6,7,7a-octahydro-1H-indazol-4-yl)oxy]-3-[(2-methyl-1-pyridin-2-yloxypropan-2-yl)amino]propan-2-ol	IC50	0.144 nM	US-11173144: Adrenergic receptor modulating compounds and methods of using the same
(2S)-1-[(3-methyl-2,3,3a,4,5,6,7,7a-octahydro-1H-indazol-4-yl)oxy]-3-(2-pyridin-2-yloxyethylamino)propan-2-ol	IC50	0.23 nM	US-11173144: Adrenergic receptor modulating compounds and methods of using the same
(2S)-1-[2-(3,4-dimethoxyphenoxy)ethylamino]-3-[(3-methyl-2,3,3a,4,5,6,7,7a-octahydro-1H-indazol-4-yl)oxy]propan-2-ol	IC50	0.38 nM	US-11173144: Adrenergic receptor modulating compounds and methods of using the same

ChEMBL bioactivities

47 potent at pChembl≥5 of 47 total, top 45 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.72	IC50	0.019	nM	CHEMBL5954552
10.62	IC50	0.024	nM	CHEMBL5946696
10.32	IC50	0.048	nM	CHEMBL5782704
10.19	IC50	0.065	nM	CHEMBL6021679
9.84	IC50	0.144	nM	CHEMBL5748424
9.64	IC50	0.23	nM	CHEMBL6028513
9.42	IC50	0.38	nM	CHEMBL6053158
9.19	IC50	0.65	nM	CHEMBL4072828
8.74	IC50	1.8	nM	CHEMBL4082775
8.48	IC50	3.3	nM	CHEMBL4083276
8.37	IC50	4.3	nM	CHEMBL4065690
8.27	IC50	5.4	nM	CHEMBL1738877
8.00	Ki	10	nM	CHEMBL3728662
8.00	Ki	10	nM	CHEMBL3728346
8.00	Ki	10	nM	CHEMBL3728772
8.00	Ki	10	nM	CHEMBL3729453
8.00	Ki	10	nM	CHEMBL3732018
7.68	IC50	21	nM	CHEMBL4095595
7.33	IC50	47	nM	BALANOL
7.00	Ki	100	nM	CHEMBL3727997
7.00	Ki	100	nM	CHEMBL3732155
7.00	Ki	100	nM	CHEMBL3729597
7.00	Ki	100	nM	CHEMBL3729044
7.00	Ki	100	nM	CHEMBL3731262
7.00	Ki	100	nM	CHEMBL3727728
7.00	Ki	100	nM	CHEMBL3729682
7.00	Ki	100	nM	CHEMBL3733136
7.00	Ki	100	nM	CHEMBL3730555
7.00	Ki	100	nM	CHEMBL3731472
7.00	Ki	100	nM	CHEMBL3729247
7.00	Ki	100	nM	CHEMBL3729970
6.85	Kd	140	nM	ERKi
6.54	IC50	290	nM	CHEMBL5712043
6.09	IC50	817	nM	STAUROSPORINE
6.07	IC50	850	nM	STAUROSPORINE
6.06	IC50	862	nM	STAUROSPORINE
6.00	Ki	1000	nM	CHEMBL3731114
6.00	Ki	1000	nM	CHEMBL3728684
6.00	Ki	1000	nM	CHEMBL3728445
6.00	Ki	1000	nM	CHEMBL3730586
6.00	Ki	1000	nM	CHEMBL3730250
6.00	Ki	1000	nM	CHEMBL3732736
6.00	IC50	1000	nM	TP-030-1
6.00	IC50	1000	nM	TP-030-2
6.00	IC50	1000	nM	TP-030n

PubChem BioAssay actives

12 with measured affinity, of 134 total; 9 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
3-(9-oxa-3,4,6,12-tetrazatricyclo[8.4.0.02,6]tetradeca-1(10),2,4,11,13-pentaen-5-ylmethylamino)-N-[[2-(trifluoromethyl)phenyl]methyl]benzamide	1457944: Inhibition of recombinant human full length GST-tagged GRK3 expressed in baculovirus using ulight topo2alpha as substrate preincubated for 60 mins followed by substrate addition measured after 10 mins by Lance TR-FRET assay	ic50	0.0006	uM
N-benzyl-3-[(3-pyridin-4-yl-1H-1,2,4-triazol-5-yl)methylamino]benzamide	1457944: Inhibition of recombinant human full length GST-tagged GRK3 expressed in baculovirus using ulight topo2alpha as substrate preincubated for 60 mins followed by substrate addition measured after 10 mins by Lance TR-FRET assay	ic50	0.0018	uM
N-benzyl-3-[(4-ethyl-5-pyridin-4-yl-1,2,4-triazol-3-yl)methylamino]benzamide	1457944: Inhibition of recombinant human full length GST-tagged GRK3 expressed in baculovirus using ulight topo2alpha as substrate preincubated for 60 mins followed by substrate addition measured after 10 mins by Lance TR-FRET assay	ic50	0.0033	uM
N-benzyl-3-[(4-methyl-3-pyridin-4-yl-1H-pyrazol-5-yl)methylamino]benzamide	1457944: Inhibition of recombinant human full length GST-tagged GRK3 expressed in baculovirus using ulight topo2alpha as substrate preincubated for 60 mins followed by substrate addition measured after 10 mins by Lance TR-FRET assay	ic50	0.0043	uM
3-[(4-methyl-5-pyridin-4-yl-1,2,4-triazol-3-yl)methylamino]-N-[[2-(trifluoromethyl)phenyl]methyl]benzamide	1457944: Inhibition of recombinant human full length GST-tagged GRK3 expressed in baculovirus using ulight topo2alpha as substrate preincubated for 60 mins followed by substrate addition measured after 10 mins by Lance TR-FRET assay	ic50	0.0054	uM
N-methyl-3-[(3-pyridin-4-yl-1H-1,2,4-triazol-5-yl)methylamino]benzamide	1457944: Inhibition of recombinant human full length GST-tagged GRK3 expressed in baculovirus using ulight topo2alpha as substrate preincubated for 60 mins followed by substrate addition measured after 10 mins by Lance TR-FRET assay	ic50	0.0210	uM
2-[2,6-dihydroxy-4-[(3R,4R)-3-[(4-hydroxybenzoyl)amino]azepan-4-yl]oxycarbonylbenzoyl]-3-hydroxybenzoic acid	464309: Inhibition of GRK3-mediated bovine tubulin phosphorylation by scintillation counting	ic50	0.0470	uM
3-[(4-methyl-5-pyridin-4-yl-1,2,4-triazol-3-yl)methylamino]-N-[[2-(trifluoromethyl)phenyl]methyl]benzamide;hydrochloride	2188159: Inhibition of human GRK3 in the presence of ATP	ic50	0.2900	uM
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	2198254: Inhibition of human GRK3 using casein as substrate preincubated for 20 mins followed by [gamma-33P]-ATP addition and measured after 120 mins by radiometric Hot-SpotSM Kinase assay	ic50	0.8170	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, affects cotreatment, decreases expression, increases expression	5
bisphenol A	decreases expression, increases methylation	2
Benzo(a)pyrene	decreases methylation, decreases expression	2
Tretinoin	increases expression	2
aristolochic acid I	decreases expression	1
FR900359	decreases phosphorylation	1
bisphenol F	increases methylation	1
terbufos	increases methylation	1
butyraldehyde	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
S-(1,2-dichlorovinyl)cysteine	increases expression, affects response to substance	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Vorinostat	decreases expression	1
Glyphosate	decreases expression	1
Doxorubicin	decreases expression	1
Fonofos	increases methylation	1
Estradiol	affects cotreatment, increases expression	1
Formaldehyde	decreases expression	1
Hydralazine	affects cotreatment, decreases expression	1
Hydrogen Peroxide	affects cotreatment, increases expression, decreases expression	1
Lipopolysaccharides	increases expression, affects response to substance	1
Parathion	increases methylation	1
Plant Extracts	affects cotreatment, increases expression	1
Theophylline	affects cotreatment, increases expression, decreases expression	1

ChEMBL screening assays

134 unique, capped per target: 134 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1037595	Binding	Residual activity of GRK3 at 1 uM by microplate scintillation counting	Substituted 2-arylbenzothiazoles as kinase inhibitors: hit-to-lead optimization. — Bioorg Med Chem

Cellosaurus cell lines

10 cell lines: 9 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_3377	HCC3153	Cancer cell line	Female
CVCL_D1MX	Abcam K-562 GRK3 KO	Cancer cell line	Female
CVCL_D2JH	Abcam Raji GRK3 KO	Cancer cell line	Male
CVCL_D7R1	Ubigene A-549 GRK3 KO	Cancer cell line	Male
CVCL_D8M6	Ubigene HCT 116 GRK3 KO	Cancer cell line	Male
CVCL_D9FW	Ubigene HEK293 GRK3 KO	Transformed cell line	Female
CVCL_SB82	HAP1 ADRBK2 (-) 1	Cancer cell line	Male
CVCL_SB83	HAP1 ADRBK2 (-) 2	Cancer cell line	Male
CVCL_SB84	HAP1 ADRBK2 (-) 3	Cancer cell line	Male
CVCL_UQ64	Abcam Jurkat GRK3 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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