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GRK4

gene
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Also known as GPRK4

Summary

GRK4 (G protein-coupled receptor kinase 4, HGNC:4543) is a protein-coding gene on chromosome 4p16.3, encoding G protein-coupled receptor kinase 4 (P32298). Specifically phosphorylates the activated forms of G protein-coupled receptors.

This gene encodes a member of the guanine nucleotide-binding protein (G protein)-coupled receptor kinase subfamily of the Ser/Thr protein kinase family. The protein phosphorylates the activated forms of G protein-coupled receptors thus initiating its deactivation. This gene has been linked to both genetic and acquired hypertension. Several transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 2868 — RefSeq curated summary.

At a glance

  • GWAS associations: 6
  • Clinical variants (ClinVar): 124 total
  • Druggable target: yes — 18 molecules with ChEMBL bioactivity
  • MANE Select transcript: NM_182982

Identifiers

Gene identifiers

FieldValue
HGNC IDHGNC:4543
Approved symbolGRK4
NameG protein-coupled receptor kinase 4
Location4p16.3
Locus typegene with protein product
StatusApproved
AliasesGPRK4
Ensembl geneENSG00000125388
Ensembl biotypeprotein_coding
OMIM137026
Entrez2868

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 8 protein_coding, 4 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000345167, ENST00000398051, ENST00000398052, ENST00000503518, ENST00000504308, ENST00000504933, ENST00000505271, ENST00000507230, ENST00000509545, ENST00000511827, ENST00000967904, ENST00000967905, ENST00000967906

RefSeq mRNA: 5 — MANE Select: NM_182982 NM_001004056, NM_001004057, NM_001350173, NM_005307, NM_182982

CCDS: CCDS33946, CCDS33947, CCDS47002, CCDS68656

Canonical transcript exons

ENST00000398052 — 16 exons

ExonStartEnd
ENSE0000085491629922152992292
ENSE0000085491830042313004334
ENSE0000085492030077363007828
ENSE0000085492930224143022451
ENSE0000085493530353863035523
ENSE0000104785430096483009711
ENSE0000116334129887272988839
ENSE0000128277529845132984608
ENSE0000128281030196413019831
ENSE0000180456030136883013828
ENSE0000204251329635712964122
ENSE0000348808530279123028001
ENSE0000354198530292013029409
ENSE0000360120530383763038513
ENSE0000362124830373743037511
ENSE0000384366430405723040760

Expression profiles

Bgee: expression breadth ubiquitous, 185 present calls, max score 95.65.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 3.6595 / max 89.3148, expressed in 1527 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter IDTPM avgSamples expressed
466682.76001367
466670.7371401
466660.139526
466650.02295

Top tissues by expression

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

TissueAnatomy IDExpression scoreQuality
left testisUBERON:000453395.65gold quality
spermCL:000001995.22gold quality
right testisUBERON:000453495.04gold quality
male germ cellCL:000001593.52gold quality
testisUBERON:000047392.86gold quality
cerebellar hemisphereUBERON:000224590.70gold quality
cerebellar cortexUBERON:000212990.51gold quality
right hemisphere of cerebellumUBERON:001489090.49gold quality
cerebellumUBERON:000203787.93gold quality
adrenal tissueUBERON:001830387.82gold quality
apex of heartUBERON:000209884.94gold quality
C1 segment of cervical spinal cordUBERON:000646984.82gold quality
adenohypophysisUBERON:000219683.95gold quality
right frontal lobeUBERON:000281083.73gold quality
cortical plateUBERON:000534383.10gold quality
pituitary glandUBERON:000000782.63gold quality
cingulate cortexUBERON:000302782.35gold quality
anterior cingulate cortexUBERON:000983582.05gold quality
primordial germ cell in gonadCL:0000670 ∩ UBERON:000099181.95gold quality
spinal cordUBERON:000224081.82gold quality
Brodmann (1909) area 9UBERON:001354081.80gold quality
body of pancreasUBERON:000115081.56gold quality
ganglionic eminenceUBERON:000402381.44gold quality
right atrium auricular regionUBERON:000663181.37gold quality
amygdalaUBERON:000187681.34gold quality
male germ line stem cell (sensu Vertebrata) in testisCL:0000089 ∩ UBERON:000047381.11gold quality
tibial nerveUBERON:000132380.78gold quality
nucleus accumbensUBERON:000188280.77gold quality
dorsolateral prefrontal cortexUBERON:000983480.36gold quality
caudate nucleusUBERON:000187380.35gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

ExperimentMarker?Max mean expression
E-ANND-3no5.67

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC

miRNA regulators (miRDB)

2 targeting GRK4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNAMax scoreAvg scoremiRNA target_count
HSA-MIR-317199.4969.06776
HSA-MIR-6814-5P99.0366.681273

Literature-anchored findings (GeneRIF, showing 40)

  • critical role of GRK4, relative to GRK2, in the homologous desensitization of D1 receptors in renal proximal tubule cells. (PMID:12164861)
  • role in phosphorylation-independent desensitization of GABA(B) receptor (PMID:12881416)
  • Genetic variation in GRK4gamma was associated with hypertension (PMID:15097232)
  • GRK4 constitutively phosphorylates the D1 receptor in the absence of agonist activation. (PMID:16338988)
  • data indicate that the R65L polymorphism of the GRK4 gene plays a role in blood pressure regulation in adolescents and young adults. (PMID:16461192)
  • The 65L allele of GRK4 gene is associated with stress-induced urinary sodium excretion. (PMID:16940246)
  • Genetic variation in Gprotein-coupled receptor kinase 4 was associated with hypertension in northern Han Chinese. (PMID:17044852)
  • We conclude that the elevated blood pressure of hGRK4gamma A142V transgenic mice is due mainly to the effect of hGRK4gamma A142V transgene acting via D(1)R and increased ROS production is not a contributor. (PMID:17259440)
  • This evidence suggests the kinase domain of GRK4gamma is responsible for GPCR regulation and GRK4 binding to inactive Galpha(s) and Gbeta may explain the constitutive activity of GRK4gamma towards Galpha(s)-coupled receptors. (PMID:18190783)
  • The GRK4 Ala142Val polymorphism did not contribute to the phenotypes in renal handling of sodium (PMID:18413491)
  • The potential implication of GRK4 promoter variation in blood pressure control in humans is unmistakable. (PMID:18711006)
  • The 4 identified genetic variants within this region exert allele-specific impact on both cell type- and stimulation-dependent transcription and may affect the expression balance of renal G protein-coupled receptor kinase 4. (PMID:18711008)
  • hypertensive African American men with a GRK4 A142 variant were less responsive to metoprolol if they had a GRK4 L65 variant (PMID:19119263)
  • GRK4, specifically the GRK4-gamma and GRK4-alpha isoforms, phosphorylates the D(3) receptor and is crucial for its signaling in human proximal tubule cells (PMID:19520868)
  • Dopamine and G protein-coupled receptor kinase 4 in the kidney: role in blood pressure regulation. (PMID:20153824)
  • The G-protein-coupled receptor kinase 4 (T-rs1024323-C and T-rs1801058-C) polymorphisms were not associated with a risk of preeclampsia in Northern Han Chinese. (PMID:20448640)
  • GRK-4 polymorphisms predict blood pressure response to dietary modification in Black subjects with mild-to-moderate hypertension. (PMID:21544086)
  • The significant association was also found for rs2960306 polymorphism in the GRK4 gene among Europeans. (PMID:22639547)
  • internalization of agonist-activated D1R is regulated by both SNX5 and GRK4, and that SNX5 is critical to the recycling of the receptor to the plasma membrane (PMID:23195037)
  • Buffalo colostrum beta-lactoglobulin inhibits VEGF-induced angiogenesis by interacting with G protein-coupled receptor kinase (PMID:23839509)
  • This study provides a mechanism by which GRK4, via regulation of arterial AT(1)R expression and function, participates in the pathogenesis of conduit vessel abnormalities in hypertension. (PMID:24218433)
  • Mutations in GRK4 gene is associated with stress fracture. (PMID:25023003)
  • the association between GRK4(142V) and a larger decrease in blood pressure with angiotensin receptor blockers in hypertensive patients. (PMID:25732908)
  • A high sodium intake markedly increased the obesity risk in variants of GRK4 A486V regardless of sex amongst Korean children. (PMID:25768006)
  • GRK4 genetic polymorphism plays an important role in the regulation of hypertension. (PMID:25870190)
  • GRK4alpha is more similar to GRK2 than GRK6. A fully ordered kinase C-tail reveals interactions linking the C-tail with important determinants of kinase activity, including the alphaB helix, alphaD helix, and the P-loop (PMID:26134571)
  • The C-terminal region of FMRP interacts with a domain of GRK4 mRNA that is folded in four stem loops. (PMID:26250109)
  • hGRK4gamma(142V) phosphorylates histone deacetylase type 1 and promotes its nuclear export to the cytoplasm, resulting in increased AT1R expression and greater pressor response to angiotensin II. (PMID:26667412)
  • Subgroup analysis for ethnicity showed that rs1024323 locus of GRK4 gene was associated with hypertension in Caucasians (OR =1.826, 95% CI =1.215-2.745, P=0.004) but not in East Asians and Africans. [meta-analysis] (PMID:26730182)
  • Thus, we provided new insight into the function of GRKs in agonist-unstimulated GPCR trafficking using a recombinant AM1 receptor and further determined the region of the CLR C-tail responsible for this GRK function. (PMID:26820533)
  • GRK4 gene variants in humans (GRK4 A>65L, A>142V, and A>486V) are associated with Hypertension in several but not all ethnic groups. GRK4 gene variants impair the function of D1R and D3R and abet the function of AT1R. These lead to enhancement of renal sodium reabsorption and impaired ability to excrete a sodium load that eventually leads to hypertension. Acknowledgments (PMID:27045027)
  • On normal salt diet, renal CuZnSOD and ECSOD proteins were similar but renal MnSOD was lower in hGRK4g486V than Non-T mice and remained low on high salt diet. hGRK4gammawild-type mice were normotensive and hGRK4g142V mice were hypertensive but both were salt-resistant and in normal redox balance. Chronic tempol treatment partially prevented the salt-sensitivity of hGRK4g486V mice. (PMID:28189851)
  • A novel function of GRK4 on triggering a p53-independent cellular senescence, which involves an intricate signaling network. (PMID:28912086)
  • Proteomics analysis of G protein-coupled receptor kinase 4-inhibited cellular growth of HEK293 cells. (PMID:31349021)
  • Renal Dopamine Receptors and Oxidative Stress: Role in Hypertension. (PMID:32349533)
  • Associations of SUCNR1, GRK4, CAMK1D gene polymorphisms and the susceptibility of type 2 diabetes mellitus and essential hypertension in a northern Chinese Han population. (PMID:33127268)
  • The role of G protein-coupled receptor kinase 4 in cardiomyocyte injury after myocardial infarction. (PMID:33280021)
  • Genetic variants of GRK4 influence circadian rhythm of blood pressure and response to candesartan in hypertensive patients. (PMID:33899625)
  • Targeted capture sequencing identifies genetic variations of GRK4 and RDH8 in Han Chinese with essential hypertension in Xinjiang. (PMID:34297769)
  • Comprehensive insights in GRK4 and hypertension: From mechanisms to potential therapeutics. (PMID:35487286)

Cross-species orthologs

5 orthologs

OrganismSymbolGene ID
danio_reriogrk4ENSDARG00000070448
mus_musculusGrk4ENSMUSG00000052783
rattus_norvegicusGrk4ENSRNOG00000011847
drosophila_melanogasterGprk2FBGN0261988
caenorhabditis_elegansWBGENE00001708

Paralogs (7): GRK3 (ENSG00000100077), GRK7 (ENSG00000114124), RSKR (ENSG00000167524), GRK2 (ENSG00000173020), GRK1 (ENSG00000185974), GRK6 (ENSG00000198055), GRK5 (ENSG00000198873)

Protein

Protein identifiers

G protein-coupled receptor kinase 4 — P32298 (reviewed: P32298)

Alternative names: G protein-coupled receptor kinase GRK4, ITI1

All UniProt accessions (2): P32298, D6REW5

UniProt curated annotations — full annotation on UniProt →

Function. Specifically phosphorylates the activated forms of G protein-coupled receptors. GRK4-alpha can phosphorylate rhodopsin and its activity is inhibited by calmodulin; the other three isoforms do not phosphorylate rhodopsin and do not interact with calmodulin. GRK4-alpha and GRK4-gamma phosphorylate DRD3. Phosphorylates ADRB2.

Subunit / interactions. Interacts with DRD3.

Subcellular location. Cytoplasm. Cell cortex.

Tissue specificity. Isoform 1, isoform 2, isoform 3, and isoform 4 are expressed in testis. Isoform 4 is expressed in myometrium.

Post-translational modifications. Palmitoylated.

Activity regulation. Inhibited by heparin.

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

Isoforms (4)

UniProt IDNamesCanonical?
P32298-11, GRK4-alpha, GRK4Dyes
P32298-22, GRK4-beta, GRK4C
P32298-33, GRK4-delta, GRK4A
P32298-44, GRK4-gamma, GRK4B

RefSeq proteins (5): NP_001004056, NP_001004057, NP_001337102, NP_005298, NP_892027* (*=MANE)

Domains & families (InterPro)

IDNameType
IPR000239GPCR_kinaseFamily
IPR000719Prot_kinase_domDomain
IPR000961AGC-kinase_CDomain
IPR008271Ser/Thr_kinase_ASActive_site
IPR011009Kinase-like_dom_sfHomologous_superfamily
IPR016137RGSDomain
IPR017441Protein_kinase_ATP_BSBinding_site
IPR036305RGS_sfHomologous_superfamily
IPR044926RGS_subdomain_2Homologous_superfamily

Pfam: PF00069, PF00615

Enzyme classification (BRENDA):

  • EC 2.7.11.16 — G-protein-coupled receptor kinase (BRENDA: 5 organisms, 89 substrates, 34 inhibitors, 5 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

SubstrateKm (mM)Measurements
ATP0.014–0.023
RHODOPSIN0.0012–0.00182

Catalyzed reactions (Rhea), 1 shown:

  • [G-protein-coupled receptor] + ATP = [G-protein-coupled receptor]-phosphate + ADP + H(+) (RHEA:12008)

UniProt features (74 total): helix 26, strand 14, sequence variant 12, turn 9, domain 3, splice variant 2, binding site 2, modified residue 2, chain 1, sequence conflict 1, region of interest 1, active site 1

Structure

Experimental structures (PDB)

1 structures.

PDBMethodResolution (Å)
4YHJX-RAY DIFFRACTION2.6

Predicted structure (AlphaFold)

ModelpLDDTFraction very-high
AF-P32298-F188.800.79

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): 312 (proton acceptor)

Ligand- & substrate-binding residues (2): 193–201; 216

Post-translational modifications (2): 1, 485

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

IDPathway
R-HSA-2514859Inactivation, recovery and regulation of the phototransduction cascade

MSigDB gene sets: 148 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_UP, MORF_RAGE, GOBP_CELLULAR_RESPONSE_TO_LIGHT_STIMULUS, GOBP_PHOTOTRANSDUCTION, GOBP_VESICLE_MEDIATED_TRANSPORT, MARTINEZ_RB1_TARGETS_UP, MISSIAGLIA_REGULATED_BY_METHYLATION_UP, GOBP_PHOTOTRANSDUCTION_VISIBLE_LIGHT, GOBP_RECEPTOR_INTERNALIZATION, GOBP_RESPONSE_TO_RADIATION, chr4p16, GNF2_CCNA1, GOBP_DETECTION_OF_LIGHT_STIMULUS, GOBP_RESPONSE_TO_ABIOTIC_STIMULUS, GOBP_DETECTION_OF_ABIOTIC_STIMULUS

GO Biological Process (6): signal transduction (GO:0007165), regulation of G protein-coupled receptor signaling pathway (GO:0008277), regulation of signal transduction (GO:0009966), regulation of opsin-mediated signaling pathway (GO:0022400), receptor internalization (GO:0031623), protein phosphorylation (GO:0006468)

GO Molecular Function (9): protein kinase activity (GO:0004672), ATP binding (GO:0005524), rhodopsin kinase activity (GO:0050254), nucleotide binding (GO:0000166), protein serine/threonine kinase activity (GO:0004674), G protein-coupled receptor kinase activity (GO:0004703), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (6): cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), cell cortex (GO:0005938), photoreceptor disc membrane (GO:0097381), sperm glycocalyx (GO:0120238)

Reactome top-level categories

Rollup of top-1 pathways:

CategoryPathways
The phototransduction cascade1

GO top-level categories

Rollup of top GO terms by namespace:

CategoryTerms
cellular anatomical structure2
cytoplasm2
cell periphery2
cell communication1
cellular process1
signaling1
regulation of cellular process1
cellular response to stimulus1
G protein-coupled receptor signaling pathway1
regulation of signal transduction1
signal transduction1
regulation of cell communication1
regulation of signaling1
regulation of response to stimulus1
regulation of G protein-coupled receptor signaling pathway1
G protein-coupled opsin signaling pathway1
regulation of response to external stimulus1
receptor-mediated endocytosis1
phosphorylation1
protein modification process1
kinase activity1
phosphotransferase activity, alcohol group as acceptor1
catalytic activity, acting on a protein1
adenyl ribonucleotide binding1
purine ribonucleoside triphosphate binding1
G protein-coupled receptor kinase activity1
nucleoside phosphate binding1
heterocyclic compound binding1
protein kinase activity1
protein serine/threonine kinase activity1
binding1
transferase activity, transferring phosphorus-containing groups1
catalytic activity1
intracellular anatomical structure1
membrane1
photoreceptor outer segment1
organelle membrane1
glycocalyx1

Protein interactions and networks

STRING

700 interactions, top by confidence (×1000):

Protein AProtein BPartner UniProtScore
GRK4GIT1Q9Y2X7998
GRK4GIT2Q14161961
GRK4ARHGEF6Q15052807
GRK4PXNP49023744
GRK4SAGP10523713
GRK4ARRB1P49407697
GRK4ARRB2P32121643
GRK4ACEP12821566
GRK4ARHGEF7Q14155557
GRK4SUCLG2Q96I99553
GRK4CYP11B2P19099551
GRK4ADRB2P07550515
GRK4RASA1P20936498
GRK4ADRB1P08588460
GRK4PEBP1P30086453

IntAct

8 interactions, top by confidence:

ABTypeScore
GRK4GRK6psi-mi:“MI:0915”(physical association)0.560
GRK4HSP90AB1psi-mi:“MI:0915”(physical association)0.400
PB2SEC15L3psi-mi:“MI:0914”(association)0.350
GRK4TCERG1psi-mi:“MI:0914”(association)0.350
GRK6ILVBLpsi-mi:“MI:0914”(association)0.350
GRK4A2ML1psi-mi:“MI:0914”(association)0.350
GRK4IKBKGpsi-mi:“MI:0407”(direct interaction)0.000

BioGRID (32): GRK4 (Reconstituted Complex), GRK4 (Reconstituted Complex), FSHR (Biochemical Activity), GRK4 (Affinity Capture-MS), S100A7 (Affinity Capture-MS), A2ML1 (Affinity Capture-MS), SERPINB4 (Affinity Capture-MS), STIP1 (Affinity Capture-MS), SERPINB3 (Affinity Capture-MS), PER1 (Affinity Capture-MS), GRK6 (Affinity Capture-MS), TCERG1 (Affinity Capture-MS), SMPD2 (Affinity Capture-MS), ANXA1 (Affinity Capture-MS), SON (Affinity Capture-MS)

ESM2 similar proteins: A0A8C0TYJ0, A0A8I5ZNK2, A5D7H2, O55047, O88506, O94806, O95747, P00535, P11273, P32298, P34947, P43249, P49137, Q08CW1, Q12959, Q13033, Q15139, Q15700, Q16644, Q1ECX4, Q28C55, Q3SYZ2, Q3UMW7, Q5PYH5, Q5PYH6, Q5R372, Q5R495, Q5RCW6, Q5XIS9, Q62101, Q62696, Q62833, Q63622, Q66H84, Q6P9R2, Q811D0, Q863I2, Q86UE8, Q8BZ03, Q8C0V0

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

3 interactions.

AEffectBMechanism
GRK4“down-regulates activity”BDKRB2phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

ClassificationCount (floor)
Pathogenic0
Likely pathogenic0
Uncertain significance94
Likely benign5
Benign2

Top pathogenic / likely-pathogenic (0)

SpliceAI

4086 predictions. Top by Δscore:

VariantEffectΔscore
4:2964121:AGGT:Adonor_loss1.0000
4:2988837:GTG:Gdonor_gain1.0000
4:2992202:T:Gacceptor_gain1.0000
4:3004220:A:AGacceptor_gain1.0000
4:3035384:A:AGacceptor_gain1.0000
4:3035385:G:GAacceptor_gain1.0000
4:3035385:GTT:Gacceptor_gain1.0000
4:3035520:TGATG:Tdonor_loss1.0000
4:3035521:GAT:Gdonor_gain1.0000
4:3035522:AT:Adonor_gain1.0000
4:3035522:ATGTA:Adonor_loss1.0000
4:3035523:TGTAA:Tdonor_loss1.0000
4:3035524:G:GGdonor_gain1.0000
4:3035524:GTA:Gdonor_loss1.0000
4:3035525:TAAG:Tdonor_loss1.0000
4:3035526:AA:Adonor_loss1.0000
4:3037373:GCCTC:Gacceptor_gain1.0000
4:2988598:A:Gdonor_gain0.9900
4:2988612:GCAAA:Gdonor_gain0.9900
4:2988613:C:Tdonor_gain0.9900
4:2988639:ATCG:Adonor_gain0.9900
4:2992201:A:AGacceptor_gain0.9900
4:2992209:A:AGacceptor_gain0.9900
4:3004221:C:Gacceptor_gain0.9900
4:3004222:T:Aacceptor_gain0.9900
4:3007509:G:Tdonor_gain0.9900
4:3007734:A:AGacceptor_gain0.9900
4:3007735:G:GGacceptor_gain0.9900
4:3007735:GA:Gacceptor_gain0.9900
4:3012706:G:GGdonor_gain0.9900

AlphaMissense

3826 scored. Top likely-pathogenic:

VariantProtein changeam_pathogenicity
4:3013735:A:CK216N0.999
4:3013735:A:TK216N0.999
4:3013734:A:TK216I0.998
4:3027930:A:CD330A0.998
4:3027930:A:TD330V0.998
4:3027931:C:AD330E0.998
4:3027931:C:GD330E0.998
4:3027930:A:GD330G0.997
4:3013728:C:AA214D0.995
4:3027921:G:CR327P0.995
4:3009670:T:CF187L0.994
4:3009671:T:CF187S0.994
4:3009672:T:AF187L0.994
4:3009672:T:GF187L0.994
4:3009703:T:CF198L0.994
4:3009705:T:AF198L0.994
4:3009705:T:GF198L0.994
4:3022437:T:CL319P0.994
4:3027929:G:CD330H0.994
4:3013734:A:CK216T0.993
4:3022432:T:AN317K0.993
4:3022432:T:GN317K0.993
4:3013733:A:GK216E0.992
4:3013823:T:CF246L0.992
4:3013825:C:AF246L0.992
4:3013825:C:GF246L0.992
4:3019705:G:AG269E0.992
4:3022440:T:CL320P0.992
4:3029248:T:AW370R0.992
4:3029248:T:CW370R0.992

dbSNP variants (sampled 300 via entrez): RS1000044579 (4:3000553 T>G), RS1000081126 (4:3004433 T>C), RS1000115863 (4:2962812 G>A,C), RS10001308 (4:2999307 C>T), RS1000150787 (4:2966942 A>C,G), RS1000173254 (4:2996094 A>G,T), RS1000199550 (4:2966413 A>AAG), RS1000256561 (4:2994243 C>T), RS1000256929 (4:2999063 G>C), RS1000257666 (4:3036330 A>G), RS1000311915 (4:3005889 C>T), RS1000366470 (4:3030643 G>C), RS1000371100 (4:3015371 C>T), RS1000435781 (4:3011951 G>A), RS1000487110 (4:2968172 A>G)

Disease associations

OMIM: gene MIM:137026 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

StudyTraitp-value
GCST007602_1Smoking behaviour (cigarettes smoked per day)1.000000e-09
GCST008156_51Hip circumference adjusted for BMI3.000000e-06
GCST009524_206Household income (MTAG)7.000000e-09
GCST009524_42Household income (MTAG)8.000000e-10
GCST011365_124Myocardial infarction5.000000e-06
GCST90002395_559Mean platelet volume1.000000e-09

EFO canonical traits (3, from GWAS)

EFO IDTrait name
EFO:0006525cigarettes per day measurement
EFO:0008039BMI-adjusted hip circumference
EFO:0009695household income

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5861 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

18 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 272,978 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

MoleculeNamePhasePatents
CHEMBL1287853FEDRATINIB43,554
CHEMBL1289926AXITINIB415,732
CHEMBL1789941RUXOLITINIB411,547
CHEMBL288441BOSUTINIB412,255
CHEMBL502835NINTEDANIB48,545
CHEMBL535SUNITINIB479,020
CHEMBL553ERLOTINIB4108,300
CHEMBL601719CRIZOTINIB414,403
CHEMBL608533MIDOSTAURIN47,259
CHEMBL522892DOVITINIB34,944
CHEMBL603469LESTAURTINIB3
CHEMBL91829RUBOXISTAURIN377
CHEMBL1721885SU-0148132363
CHEMBL230011TG100-11521,504
CHEMBL475251R-4062762
CHEMBL572878TOZASERTIB22,998
CHEMBL1908394GSK-46136411,093
CHEMBL1908397KW-24491622

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

PharmGKB clinical annotations

3 annotations.

VariantTypeLevelDrugsPhenotypes
rs1024323Efficacy3metoprololHypertension;Kidney Disorder;Nephrosclerosis
rs1024323Toxicity3atenolol;verapamilCoronary Artery Disease;Hypertension
rs1801058Efficacy3metoprololhypertensive nephrosclerosis

PharmGKB variants

3 variants.

VariantGenesLevelScore#Clin annotsDrugs
rs1024323GRK431.752metoprolol;atenolol;verapamil
rs1801058GRK430.501metoprolol
rs2960306GRK40.000

PharmGKB dosing guidelines

1 guidelines.

SourceDrugGuidelineDosing?Recommendation?
CPICacebutolol;atenolol;betaxolol;bisoprolol;carvedilol;esmolol;labetalol;metoprolol;nadolol;nebivolol;pindolol;propranolol;sotalolAnnotation of CPIC Guideline for acebutolol, atenolol, betaxolol, bisoprolol, carvedilol, esmolol, labetalol, metoprolol, nadolol, nebivolol, pindolol, propranolol, sotalol and ADRA2C, ADRB1, GRK4, GRK5

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — GRK4 subfamily

Most potent curated ligand interactions (1 total), top 1:

LigandActionAffinityParameter
balanolInhibition6.59pIC50

ChEMBL bioactivities

41 potent at pChembl≥5 of 43 total, top 38 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChemblTypeValueUnitMolecule
7.92Kd12nMLESTAURTINIB
7.77Kd17nMNINTEDANIB
7.66IC5022nMCHEMBL4877302
7.43Kd37nMSTAUROSPORINE
7.16IC5069.9nMSTAUROSPORINE
7.15Kd71nMKW-2449
7.08IC5083.8nMSTAUROSPORINE
7.01IC5097nMCHEMBL4854871
7.01Kd97nMDOVITINIB
6.96Kd110nMMIDOSTAURIN
6.95IC50113nMSTAUROSPORINE
6.85Kd140nMSUNITINIB
6.77Kd170nMFEDRATINIB
6.72IC50190nMCHEMBL4847703
6.58IC50260nMCHEMBL4568087
6.58IC50260nMBALANOL
6.43Kd370nMSU-014813
6.40Kd400nMTOZASERTIB
6.38Kd420nMPHA-665752
6.35Kd450nMR-406
6.23Kd590nMRUBOXISTAURIN
6.17IC50670nMCHEMBL4552628
6.00IC501000nMTP-030-1
6.00IC501000nMTP-030-2
6.00IC501000nMTP-030n
5.85Kd1400nMCHEMBL379218
5.66Kd2200nMCHEMBL1908395
5.64Kd2300nMAXITINIB
5.55Kd2800nMGSK-461364
5.54Kd2900nMCGP-52421
5.46Kd3500nMTAE-684
5.38Kd4200nMCRIZOTINIB
5.31Kd4900nMBOSUTINIB
5.28IC505300nMCHEMBL4569508
5.21Kd6100nMRUXOLITINIB
5.21Kd6200nMTG100-115
5.14Kd7300nMERLOTINIB
5.00IC501e+04nMCHEMBL3884319

PubChem BioAssay actives

39 with measured affinity, of 218 total; 33 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

CompoundAssayTypeValueUnit
(15S,16S,18R)-16-hydroxy-16-(hydroxymethyl)-15-methyl-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaen-3-one507964: Binding affinity to GRK4kd0.0120uM
methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate624739: Binding constant for GRK4 kinase domainkd0.0170uM
2-N-[(4-chloro-2-methoxyphenyl)methyl]-4-N-(5-ethyl-1H-pyrazol-3-yl)-5-methoxyquinazoline-2,4-diamine1751898: Inhibition of human GRK4 using casein as substrate in presence of [gamma33P]ATP by radiometric hotspot kinase assayic500.0220uM
(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-one624739: Binding constant for GRK4 kinase domainkd0.0370uM
[4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone624739: Binding constant for GRK4 kinase domainkd0.0710uM
4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one624739: Binding constant for GRK4 kinase domainkd0.0970uM
4-N-(5-ethyl-1H-pyrazol-3-yl)-2-N-[(1S)-1-(5-fluoro-2-pyridinyl)ethyl]-5-methoxyquinazoline-2,4-diamine1751898: Inhibition of human GRK4 using casein as substrate in presence of [gamma33P]ATP by radiometric hotspot kinase assayic500.0970uM
Midostaurin507964: Binding affinity to GRK4kd0.1100uM
Sunitinib507964: Binding affinity to GRK4kd0.1400uM
Fedratinib624739: Binding constant for GRK4 kinase domainkd0.1700uM
4-N-(5-ethyl-1H-pyrazol-3-yl)-2-N-[(5-fluoro-2-pyridinyl)methyl]-5-methoxyquinazoline-2,4-diamine1751898: Inhibition of human GRK4 using casein as substrate in presence of [gamma33P]ATP by radiometric hotspot kinase assayic500.1900uM
2-[2,6-dihydroxy-4-[(3R,4R)-3-[(4-hydroxybenzoyl)amino]azepan-4-yl]oxycarbonylbenzoyl]-3-hydroxybenzoic acid464310: Inhibition of GRK4-mediated bovine tubulin phosphorylation by scintillation countingic500.2600uM
N-[(1R,2S)-2-aminocyclohexyl]-4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]thiophene-2-carboxamide1637079: Inhibition of full-length recombinant human GST-tagged GRK4 expressed in baculovirus expression system by Z’-LYTE assayic500.2600uM
5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide624739: Binding constant for GRK4 kinase domainkd0.3700uM
N-[4-[4-(4-methylpiperazin-1-yl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]sulfanylphenyl]cyclopropanecarboxamide624739: Binding constant for GRK4 kinase domainkd0.4000uM
(3Z)-5-[(2,6-dichlorophenyl)methylsulfonyl]-3-[[3,5-dimethyl-4-[(2R)-2-(pyrrolidin-1-ylmethyl)pyrrolidine-1-carbonyl]-1H-pyrrol-2-yl]methylidene]-1H-indol-2-one624739: Binding constant for GRK4 kinase domainkd0.4200uM
6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one624739: Binding constant for GRK4 kinase domainkd0.4500uM
(18S)-18-[(dimethylamino)methyl]-17-oxa-4,14,21-triazahexacyclo[19.6.1.17,14.02,6.08,13.022,27]nonacosa-1(28),2(6),7(29),8,10,12,22,24,26-nonaene-3,5-dione624739: Binding constant for GRK4 kinase domainkd0.5900uM
N-[(1R,6R)-6-amino-2,2-difluorocyclohexyl]-4-(6-chloropyrazolo[1,5-a]pyrimidin-3-yl)-5-methylthiophene-2-carboxamide1637079: Inhibition of full-length recombinant human GST-tagged GRK4 expressed in baculovirus expression system by Z’-LYTE assayic500.6700uM
Momelotinib2183895: Inhibition of GRK4 (unknown origin)ic501.0000uM
(2S)-1-[[5-(3-methyl-2H-indazol-5-yl)-3-pyridinyl]oxy]-3-phenylpropan-2-amine624739: Binding constant for GRK4 kinase domainkd1.4000uM
5-cyano-N-[2-(cyclohexen-1-yl)-4-[1-[2-(dimethylamino)acetyl]piperidin-4-yl]phenyl]-1H-imidazole-2-carboxamide;hydrochloride624739: Binding constant for GRK4 kinase domainkd2.2000uM
Axitinib624739: Binding constant for GRK4 kinase domainkd2.3000uM
5-[6-[(4-methylpiperazin-1-yl)methyl]benzimidazol-1-yl]-3-[(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy]thiophene-2-carboxamide624739: Binding constant for GRK4 kinase domainkd2.8000uM
N-[(2S,3R,4R,6R,18S)-18-hydroxy-3-methoxy-2-methyl-16-oxo-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-4-yl]-N-methylbenzamide507964: Binding affinity to GRK4kd2.9000uM
5-chloro-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine624739: Binding constant for GRK4 kinase domainkd3.5000uM
Crizotinib624739: Binding constant for GRK4 kinase domainkd4.2000uM
Bosutinib624739: Binding constant for GRK4 kinase domainkd4.9000uM
4-[6-[4-(2-piperidin-1-ylethoxy)phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]-N-(2,2,2-trifluoroethyl)thiophene-2-carboxamide1637079: Inhibition of full-length recombinant human GST-tagged GRK4 expressed in baculovirus expression system by Z’-LYTE assayic505.3000uM
Ruxolitinib624739: Binding constant for GRK4 kinase domainkd6.1000uM
3-[2,4-diamino-7-(3-hydroxyphenyl)pteridin-6-yl]phenol624739: Binding constant for GRK4 kinase domainkd6.2000uM
Erlotinib624739: Binding constant for GRK4 kinase domainkd7.3000uM
2-anilino-7-[(1S)-4-hydroxy-2,3-dihydro-1H-inden-1-yl]-5,5-dimethylpyrrolo[2,3-d]pyrimidin-6-one1336068: Inhibition of human recombinant full length GST-tagged GRK4 expressed in baculovirus expression systemic5010.0000uM

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

ChemicalActions (top 5)PubMed papers
Valproic Acidaffects reaction, increases expression, affects cotreatment, affects expression3
Arsenic Trioxideincreases expression2
Aflatoxin B1increases methylation, decreases methylation2
triphenyl phosphateaffects expression1
sodium arseniteaffects methylation1
di-n-butylphosphoric acidaffects expression1
CGP 52608affects binding, increases reaction1
abrineincreases expression1
darinaparsinincreases expression, decreases reaction1
Sunitinibincreases expression1
Acetaminophendecreases expression1
Benzo(a)pyrenedecreases methylation1
Hydralazineaffects cotreatment, increases expression1
Methotrexateincreases expression1
Metoprololaffects response to substance1
Oxygendecreases reaction, increases expression1
Phthalic Acidsdecreases methylation1
Silicon Dioxidedecreases expression1
Antirheumatic Agentsincreases expression1
Cadmium Chlorideincreases expression1

ChEMBL screening assays

139 unique, capped per target: 139 binding

Representative assays (with source publication via chembl_document):

Assay IDTypeDescriptionSource paper
CHEMBL1037596BindingResidual activity of GRK4 at 1 uM by microplate scintillation countingSubstituted 2-arylbenzothiazoles as kinase inhibitors: hit-to-lead optimization. — Bioorg Med Chem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

CellosaurusNameCategorySex
CVCL_B1T9Abcam HeLa GRK4 KOCancer cell lineFemale

Clinical trials (associated diseases)

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

No linked Atlas pages yet — the cross-entity mesh grows as the corpus expands.

About this page

Generated deterministically by Sugi Atlas from primary biomedical databases via BioBTree. Every record on this page traces to a primary source.

Generated
Atlas version
v1.1.4
BioBTree
v2.0.2

Sources 80

This page pulls from 80 datasets indexed by BioBTree:

alphafoldalphamissenseantibodybgeebgee_evidencebindingdbbiogrid_interactionbrendabrenda_kineticsccdscellosauruschembl_activitychembl_assaychembl_documentchembl_moleculechembl_targetciviccivic_evidenceclingen_dosageclingen_gene_validityclinical_trialsclinvarcollectrictd_gene_interactiondbsnpdepmapdiamond_similarityefoensemblentrezesm2_similarityexonfantom5_genefantom5_promotergenccgenerifgogoparentgtopdbgtopdb_interactiongwasgwas_studyhgnchpointactinterprointogenjasparmeshmimmirdbmondomsigdborphanetorthologparalogpatent_compoundpdbpfampharmgkb_clinicalpharmgkb_genepharmgkb_guidelinepharmgkb_variantpubchempubchem_activitypubchem_assaypubmedreactomereactomeparentrefseqrhearnacentralscxa_expressionscxa_gene_experimentsignorspliceaistring_interactiontranscriptufeatureuniprot