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Insulin receptor

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Target not currently curated in GtoImmuPdb

Target id: 1800

Nomenclature: Insulin receptor

Abbreviated Name: InsR

Family: Type II RTKs: Insulin receptor family

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 1382 19p13.2 INSR insulin receptor
Mouse 1 1372 8 1.82 cM Insr insulin receptor
Rat 1 1383 12p12 Insr insulin receptor
Previous and Unofficial Names Click here for help
IR | IR-A | IR-B | CD220
Database Links Click here for help
Alphafold P06213 (Hs), P15208 (Mm), P15127 (Rn)
BRENDA 2.7.10.1
CATH/Gene3D 3.80.20.20, 2.60.40.10
ChEMBL Target CHEMBL1981 (Hs), CHEMBL3187 (Mm), CHEMBL5486 (Rn)
DrugBank Target P06213 (Hs)
Ensembl Gene ENSG00000171105 (Hs), ENSMUSG00000005534 (Mm), ENSRNOG00000029986 (Rn)
Entrez Gene 3643 (Hs), 16337 (Mm), 24954 (Rn)
Human Protein Atlas ENSG00000171105 (Hs)
KEGG Enzyme 2.7.10.1
KEGG Gene hsa:3643 (Hs), mmu:16337 (Mm), rno:24954 (Rn)
OMIM 147670 (Hs)
Orphanet ORPHA122664 (Hs)
Pharos P06213 (Hs)
RefSeq Nucleotide NM_000208 (Hs), NM_010568 (Mm), NM_017071 (Rn)
RefSeq Protein NP_000199 (Hs), NP_034698 (Mm), NP_058767 (Rn)
UniProtKB P06213 (Hs), P15208 (Mm), P15127 (Rn)
Wikipedia INSR (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the insulin receptor kinase in complex with IRS2 KRLB peptide
PDB Id:  3BU3
Resolution:  1.65Å
Species:  Human
References:  15
Image of receptor 3D structure from RCSB PDB
Description:  CRYSTAL STRUCTURE OF THE TYROSINE KINASE DOMAIN OF THE HUMAN INSULIN RECEPTOR
PDB Id:  1IRK
Resolution:  2.1Å
Species:  Human
References:  6
Enzyme Reaction Click here for help
EC Number: 2.7.10.1
Natural/Endogenous Ligands Click here for help
insulin {Sp: Human}
Endogenous agonist rank potency
insulin (INS, P01308) > insulin-like growth factor 1 (IGF1, P05019)

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
myricetin Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 5.6 pKi 4
⤷ pKi 5.6 (Ki 2.6x10-6 M) [4]
GSK-1838705A Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.8 pIC50 11
⤷ pIC50 8.8 (IC50 1.6x10-9 M) [11]
ceritinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.1 pIC50 8
⤷ pIC50 8.1 (IC50 7x10-9 M) [8]
NVP-TAE 226 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.2 – 7.6 pIC50 7
⤷ pIC50 7.2 – 7.6 (IC50 6.1x10-8 – 2.6x10-8 M) [7]
Description: In vitro kinase assay with recombinant kinase domains and peptide substrates.
BMS-536924 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.1 pIC50 13
⤷ pIC50 7.1 (IC50 7.3x10-8 M) [13]
linsitinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.1 pIC50 9
⤷ pIC50 7.1 (IC50 7.5x10-8 M) [9]
Description: In a kinase screening selectivity assay.
brigatinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.7 pIC50 5
⤷ pIC50 6.7 (IC50 1.96x10-7 M) [5]
compound 15 [PMID: 24900237] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.2 pIC50 10
⤷ pIC50 6.2 (IC50 5.97x10-7 M) [10]
dovitinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 5.7 pIC50 12
⤷ pIC50 5.7 (IC50 2x10-6 M) [12]
Agonists
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
insulin-like growth factor 1 {Sp: Human} Peptide Approved drug Click here for species-specific activity table Ligand is endogenous in the given species Hs Agonist - -
⤷
insulin {Sp: Human} Peptide Approved drug Primary target of this compound Ligand is endogenous in the given species Hs Agonist - -
⤷
DiscoveRx KINOMEscan® screen Click here for help
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
http://www.discoverx.com/services/drug-discovery-development-services/kinase-profiling/kinomescan
Reference: 2,14
Key to terms and symbols Click column headers to sort
Target used in screen: INSR
Ligand Sp. Type Action Value Parameter
GSK-1838705A Small molecule or natural product Hs Inhibitor Inhibition 8.8 pKd
NVP-TAE684 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.6 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.0 pKd
foretinib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.7 pKd
JNJ-28312141 Small molecule or natural product Hs Inhibitor Inhibition 6.5 pKd
crizotinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.5 pKd
KW-2449 Small molecule or natural product Hs Inhibitor Inhibition 6.4 pKd
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 6.3 pKd
tozasertib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.2 pKd
fedratinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 6.1 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen Click here for help
A screen profiling 158 kinase inhibitors (Calbiochem Protein Kinase Inhibitor Library I and II, catalogue numbers 539744 and 539745) for their inhibitory activity at 1µM and 10µM against 234 human recombinant kinases using the EMD Millipore KinaseProfilerTM service.

A screen profiling the inhibitory activity of 178 commercially available kinase inhibitors at 0.5µM against a panel of 300 recombinant protein kinases using the Reaction Biology Corporation Kinase HotspotSM platform.

http://www.millipore.com/techpublications/tech1/pf3036
http://www.reactionbiology.com/webapps/main/pages/kinase.aspx

Reference: 1,3
Key to terms and symbols Click column headers to sort
Target used in screen: IR (activated)/nd
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 5.5 0.5
K-252a Small molecule or natural product Hs Inhibitor Inhibition 7.0 0.0
SU11652 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.0 0.0
indirubin derivative E804 Small molecule or natural product Hs Inhibitor Inhibition 10.0 4.0
isogranulatimide Small molecule or natural product Hs Inhibitor Inhibition 31.0 19.0
purvalanol A Small molecule or natural product Hs Inhibitor Inhibition 34.0 4.0
indirubin-3'-monoxime Small molecule or natural product Hs Inhibitor Inhibition 35.0 19.0
GSK-3 inhibitor XIII Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 36.0 7.0
Cdk2 inhibitor IV Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 47.0 7.0
semaxanib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 49.0 44.0
Target used in screen: IR/IR
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 3.1 19.5 3.0
SB 218078 Small molecule or natural product Hs Inhibitor Inhibition 17.2 94.0 79.0
isogranulatimide Small molecule or natural product Hs Inhibitor Inhibition 17.9 10.0 15.0
SU11652 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 30.1 32.0 6.0
GSK-3 inhibitor XIII Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 31.6 16.0 5.0
K-252a Small molecule or natural product Hs Inhibitor Inhibition 32.2 42.0 20.0
PDK1/Akt/Flt dual pathway inhibitor Small molecule or natural product Hs Inhibitor Inhibition 32.3 121.0 102.0
tozasertib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 43.5
indirubin derivative E804 Small molecule or natural product Hs Inhibitor Inhibition 44.9 17.0 4.0
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 51.2
Displaying the top 10 most potent ligands  View all ligands in screen »
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Diabetes mellitus, insulin-resistant, with acanthosis nigricans, type A
Synonyms: Insulin-resistance syndrome type A [Orphanet: ORPHA2297]
OMIM: 610549
Orphanet: ORPHA2297
Disease:  Diabetes mellitus, noninsulin-dependent; NIDDM
Synonyms: Diabetes mellitus, Type II; T2D [OMIM: 125853]
Maturity onset diabetes
Type 2 diabetes mellitus [Disease Ontology: DOID:9352]
Disease Ontology: DOID:9352
OMIM: 125853
Disease:  Donohue syndrome
Synonyms: Leprechaunism [Orphanet: ORPHA508]
Disease Ontology: DOID:0050470
OMIM: 246200
Orphanet: ORPHA508
Disease:  Hyperinsulinemic hypoglycemia, familial, 5; HHF5
Synonyms: Hyperinsulinemic hypoglycemia [Disease Ontology: DOID:13317]
Hyperinsulinism due to INSR deficiency [Orphanet: ORPHA263458]
Disease Ontology: DOID:13317
OMIM: 609968
Orphanet: ORPHA263458
Disease:  Rabson-Mendenhall syndrome
Synonyms: Pineal hyperplasia, insulin-resistant diabetes mellitus, and somatic abnormalities [OMIM: 262190]
OMIM: 262190
Orphanet: ORPHA769

References

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1. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat Biotechnol, 29 (11): 1039-45. [PMID:22037377]

2. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol, 29 (11): 1046-51. [PMID:22037378]

3. Gao Y, Davies SP, Augustin M, Woodward A, Patel UA, Kovelman R, Harvey KJ. (2013) A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. Biochem J, 451 (2): 313-28. [PMID:23398362]

4. Hagiwara M, Inoue S, Tanaka T, Nunoki K, Ito M, Hidaka H. (1988) Differential effects of flavonoids as inhibitors of tyrosine protein kinases and serine/threonine protein kinases. Biochem Pharmacol, 37 (15): 2987-92. [PMID:3164998]

5. Huang WS, Liu S, Zou D, Thomas M, Wang Y, Zhou T, Romero J, Kohlmann A, Li F, Qi J et al.. (2016) Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase. J Med Chem, 59 (10): 4948-64. [PMID:27144831]

6. Hubbard SR, Wei L, Ellis L, Hendrickson WA. (1994) Crystal structure of the tyrosine kinase domain of the human insulin receptor. Nature, 372 (6508): 746-54. [PMID:7997262]

7. Liu TJ, LaFortune T, Honda T, Ohmori O, Hatakeyama S, Meyer T, Jackson D, de Groot J, Yung WK. (2007) Inhibition of both focal adhesion kinase and insulin-like growth factor-I receptor kinase suppresses glioma proliferation in vitro and in vivo. Mol Cancer Ther, 6 (4): 1357-67. [PMID:17431114]

8. Marsilje TH, Pei W, Chen B, Lu W, Uno T, Jin Y, Jiang T, Kim S, Li N, Warmuth M et al.. (2013) Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials. J Med Chem, 56 (14): 5675-90. [PMID:23742252]

9. Mulvihill MJ, Cooke A, Rosenfeld-Franklin M, Buck E, Foreman K, Landfair D, O'Connor M, Pirritt C, Sun Y, Yao Y et al.. (2009) Discovery of OSI-906: a selective and orally efficacious dual inhibitor of the IGF-1 receptor and insulin receptor. Future Med Chem, 1 (6): 1153-71. [PMID:21425998]

10. Ott GR, Tripathy R, Cheng M, McHugh R, Anzalone AV, Underiner TL, Curry MA, Quail MR, Lu L, Wan W et al.. (2010) Discovery of a potent inhibitor of anaplastic lymphoma kinase with in vivo antitumor activity. ACS Med Chem Lett, 1 (9): 493-8. [PMID:24900237]

11. Sabbatini P, Korenchuk S, Rowand JL, Groy A, Liu Q, Leperi D, Atkins C, Dumble M, Yang J, Anderson K et al.. (2009) GSK1838705A inhibits the insulin-like growth factor-1 receptor and anaplastic lymphoma kinase and shows antitumor activity in experimental models of human cancers. Mol Cancer Ther, 8 (10): 2811-20. [PMID:19825801]

12. Trudel S, Li ZH, Wei E, Wiesmann M, Chang H, Chen C, Reece D, Heise C, Stewart AK. (2005) CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma. Blood, 105 (7): 2941-8. [PMID:15598814]

13. Wittman M, Carboni J, Attar R, Balasubramanian B, Balimane P, Brassil P, Beaulieu F, Chang C, Clarke W, Dell J et al.. (2005) Discovery of a (1H-benzoimidazol-2-yl)-1H-pyridin-2-one (BMS-536924) inhibitor of insulin-like growth factor I receptor kinase with in vivo antitumor activity. J Med Chem, 48 (18): 5639-43. [PMID:16134929]

14. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al.. (2010) Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem Biol, 17 (11): 1241-9. [PMID:21095574]

15. Wu J, Tseng YD, Xu CF, Neubert TA, White MF, Hubbard SR. (2008) Structural and biochemical characterization of the KRLB region in insulin receptor substrate-2. Nat Struct Mol Biol, 15 (3): 251-8. [PMID:18278056]

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