Insulin receptor

Target id: 1800

Nomenclature: Insulin receptor

Abbreviated Name: InsR

Family: Type II RTKs: Insulin receptor family

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 1382 19p13.3-p13.2 INSR insulin receptor
Mouse 1 1372 8 Insr insulin receptor
Rat 1 1384 12q12 Insr insulin receptor
Previous and Unofficial Names
IR
IR-A
IR-B
CD220
Database Links
BRENDA
Ensembl Gene
Entrez Gene
ExplorEnz
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
Human Protein Reference Database
InterPro
KEGG Enzyme
KEGG Gene
NeXtProt
OMIM
Orphanet
PhosphoSitePlus
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniGene
UniProtKB
Wikipedia
Selected 3D Structures
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:  11
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:  4
Enzyme Reaction
EC Number: 2.7.10.1
Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
GSK-1838705A Hs Inhibition 8.8 pIC50 8
pIC50 8.8 (IC50 1.6x10-9 M) [8]
ceritinib Hs Inhibition 8.15 pIC50 5
pIC50 8.15 (IC50 7x10-9 M) [5]
linsitinib Hs Inhibition 7.46 pIC50 6
pIC50 7.46 (IC50 3.5x10-8 M) [6]
compound 15 [PMID 24900237] Hs Inhibition 6.22 pIC50 7
pIC50 6.22 (IC50 5.97x10-7 M) [7]
dovitinib Hs Inhibition 5.7 pIC50 9
pIC50 5.7 (IC50 2x10-6 M) [9]
Agonists
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Affinity Units Reference
insulin {Sp: Human} Hs Agonist - -
DiscoveRx KINOMEscan® screen
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: 2,10

Key to terms and symbols Click column headers to sort
Target used in screen: INSR
Ligand Sp. Type Action Affinity Units
GSK-1838705A Hs Inhibitor Inhibition 8.77 pKd
NVP-TAE684 Hs Inhibitor Inhibition 8.62 pKd
staurosporine Hs Inhibitor Inhibition 6.96 pKd
foretinib Hs Inhibitor Inhibition 6.68 pKd
JNJ-28312141 Hs Inhibitor Inhibition 6.48 pKd
crizotinib Hs Inhibitor Inhibition 6.47 pKd
KW-2449 Hs Inhibitor Inhibition 6.4 pKd
sunitinib Hs Inhibitor Inhibition 6.3 pKd
tozasertib Hs Inhibitor Inhibition 6.2 pKd
fedratinib Hs Inhibitor Inhibition 6.07 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen
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 Hs Inhibitor Inhibition 5.5 0.5
K-252a Hs Inhibitor Inhibition 7.0 0.0
SU11652 Hs Inhibitor Inhibition 8.0 0.0
indirubin derivative E804 Hs Inhibitor Inhibition 10.0 4.0
isogranulatimide Hs Inhibitor Inhibition 31.0 19.0
purvalanol A Hs Inhibitor Inhibition 34.0 4.0
indirubin-3'-monoxime Hs Inhibitor Inhibition 35.0 19.0
GSK-3 inhibitor XIII Hs Inhibitor Inhibition 36.0 7.0
Cdk2 inhibitor IV Hs Inhibitor Inhibition 47.0 7.0
semaxanib 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 Hs Inhibitor Inhibition 3.1 19.5 3.0
SB 218078 Hs Inhibitor Inhibition 17.2 94.0 79.0
isogranulatimide Hs Inhibitor Inhibition 17.9 10.0 15.0
SU11652 Hs Inhibitor Inhibition 30.1 32.0 6.0
GSK-3 inhibitor XIII Hs Inhibitor Inhibition 31.6 16.0 5.0
K-252a Hs Inhibitor Inhibition 32.2 42.0 20.0
PDK1/Akt/Flt dual pathway inhibitor Hs Inhibitor Inhibition 32.3 121.0 102.0
tozasertib Hs Inhibitor Inhibition 43.5
indirubin derivative E804 Hs Inhibitor Inhibition 44.9 17.0 4.0
sunitinib Hs Inhibitor Inhibition 51.2
Displaying the top 10 most potent ligands  View all ligands in screen »
Clinically-Relevant Mutations and Pathophysiology
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: type 2 diabetes mellitus [Disease Ontology: DOID:9352]
Disease Ontology: DOID:9352
OMIM: 125853
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:  Leprechaunism
OMIM: 246200
Orphanet: ORPHA508
Disease:  Rabson-Mendenhall syndrome
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. Hubbard SR, Wei L, Ellis L, Hendrickson WA. (1994) Crystal structure of the tyrosine kinase domain of the human insulin receptor. Nature372 (6508): 746-54. [PMID:7997262]

5. 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]

6. 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 Chem1 (6): 1153-71. [PMID:21425998]

7. 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 Lett1 (9): 493-8. [PMID:24900237]

8. 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]

9. 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. Blood105 (7): 2941-8. [PMID:15598814]

10. 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]

11. 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]

How to cite this page

Type II RTKs: Insulin receptor family: Insulin receptor. Last modified on 25/02/2015. Accessed on 19/04/2015. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1800.