EzCatDB: M00136
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DB codeM00136
RLCP classification3.103.130000.358 : Transfer
CATH domainDomain 13.80.20.20 : 24 nucleotide stem-loop, u2 snrnp hairpin iv. U2 a'; Chain A
Domain 22.10.220.10 : Hormone Receptor, Insulin-like Growth Factor Receptor 1; Chain A domain 2
Domain 33.80.20.20 : 24 nucleotide stem-loop, u2 snrnp hairpin iv. U2 a'; Chain A
Domain 4-.-.-.-
Domain 52.60.40.30 : Immunoglobulin-like
Domain 63.30.200.20 : Phosphorylase Kinase; domain 1
Domain 71.10.510.10 : Transferase(Phosphotransferase); domain 1Catalytic domain
E.C.2.7.10.1

CATH domainRelated DB codes (homologues)
1.10.510.10 : Transferase(Phosphotransferase); domain 1M00125,M00124,M00131,T00224,M00127,M00129,M00130,M00132,M00196,M00197,M00198,M00304,M00323,M00325,M00326,M00327,M00328,M00329,M00330,M00331,M00332,M00333,M00335,M00339,M00344
2.60.40.30 : Immunoglobulin-likeM00124,M00134,M00129,M00149,M00192
3.30.200.20 : Phosphorylase Kinase; domain 1M00125,M00124,M00131,T00224,M00127,M00129,M00130,M00132,M00196,M00197,M00198,M00304,M00323,M00325,M00326,M00327,M00328,M00329,M00330,M00331,M00332,M00333,M00335,M00339,M00344,D00298

Enzyme Name
UniProtKBKEGG

P08069
Protein nameInsulin-like growth factor 1 receptor (EC 2.7.10.1) (Insulin-like growth factor I receptor) (IGF-I receptor)AltName: CD_antigen=CD221;receptor protein-tyrosine kinase
AATK
AATYK
AATYK2
AATYK3
ACH
ALK
anaplastic lymphoma kinase
ARK
ATP:protein-tyrosine O-phosphotransferase (ambiguous)
AXL
Bek
Bfgfr
BRT
Bsk
C-FMS
CAK
CCK4
CD115
CD135
CDw135
Cek1
Cek10
Cek11
Cek2
Cek3
Cek5
Cek6
Cek7
CFD1
CKIT
CSF1R
DAlk
DDR1
DDR2
Dek
DKFZp434C1418
Drosophila Eph kinase
DRT
DTK
Ebk
ECK
EDDR1
Eek
EGFR
Ehk2
Ehk3
Elk
EPH
EPHA1
EPHA2
EPHA6
EPHA7
EPHA8
EPHB1
EPHB2
EPHB3
EPHB4
EphB5
ephrin-B3 receptor tyrosine kinase
EPHT
EPHT2
EPHT3
EPHX
ERBB
ERBB1
ERBB2
ERBB3
ERBB4
ERK
Eyk
FGFR1
FGFR2
FGFR3
FGFR4
FLG
FLK1
FLK2
FLT1
FLT2
FLT3
FLT4
FMS
Fv2
HBGFR
HEK11
HEK2
HEK3
HEK5
HEK6
HEP
HER2
HER3
HER4
HGFR
HSCR1
HTK
IGF1R
INSR
INSRR
insulin receptor protein-tyrosine kinase
IR
IRR
JTK12
JTK13
JTK14
JWS
K-SAM
KDR
KGFR
KIA0641
KIAA1079
KIAA1459
Kil
Kin15
Kin16
KIT
KLG
LTK
MCF3
Mdk1
Mdk2
Mdk5
MEhk1
MEN2A/B
Mep
MER
MERTK
MET
Mlk1
Mlk2
Mrk
MST1R
MTC1
MUSK
Myk1
N-SAM
NEP
NET
Neu
neurite outgrowth regulating kinase
NGL
NOK
nork
novel oncogene with kinase-domain
Nsk2
NTRK1
NTRK2
NTRK3
NTRK4
NTRKR1
NTRKR2
NTRKR3
Nuk
NYK
PCL
PDGFR
PDGFRA
PDGFRB
PHB6
protein-tyrosine kinase (ambiguous)
protein tyrosine kinase (ambiguous)
PTK
PTK3
PTK7
receptor protein tyrosine kinase
RET
RON
ROR1
ROR2
ROS1
RSE
RTK
RYK
SEA
Sek2
Sek3
Sek4
Sfr
SKY
STK
STK1
TEK
TIE
TIE1
TIE2
TIF
TKT
TRK
TRKA
TRKB
TRKC
TRKE
TYK1
TYRO10
Tyro11
TYRO3
Tyro5
Tyro6
TYRO7
UFO
VEGFR1
VEGFR2
VEGFR3
Vik
YK1
Yrk
SynonymsNone
ContainsInsulin-like growth factor 1 receptor alpha chain
Insulin-like growth factor 1 receptor beta chain
RefSeqNP_000866.1 (Protein)
NM_000875.3 (DNA/RNA sequence)
PfamPF00041 (fn3)
PF00757 (Furin-like)
PF07714 (Pkinase_Tyr)
PF01030 (Recep_L_domain)
[Graphical view]


UniProtKB:Accession NumberP08069
Entry nameIGF1R_HUMAN
ActivityATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
SubunitTetramer of 2 alpha and 2 beta chains linked by disulfide bonds. The alpha chains contribute to the formation of the ligand- binding domain, while the beta chain carries the kinase domain. Interacts with PIK3R1 and with the PTB/PID domains of IRS1 and SHC1 in vitro when autophosphorylated on tyrosine residues.
Subcellular locationMembrane, Single-pass type I membrane protein.
Cofactor

Compound table: links to PDB-related databases & PoSSuM

CofactorsSubstratesProducts
KEGG-idC00305C00002C00585C00008C01167
CompoundMagnesiumATP[Protein]-L-tyrosineADP[Protein]-L-tyrosine phosphate
Typedivalent metal (Ca2+, Mg2+)amine group,nucleotidearomatic ring (only carbon atom),peptide/proteinamine group,nucleotidearomatic ring (only carbon atom),peptide/protein,phosphate group/phosphate ion
ChEBI18420
15422

16761

PubChem888
5957

6022

             
1igrA01UnboundUnboundUnboundUnboundUnbound
1igrA02UnboundUnboundUnboundUnboundUnbound
1igrA03UnboundUnboundUnboundUnboundUnbound
1jqhA01Bound:_MGAnalogue:ANPUnboundUnboundUnbound
1jqhB01UnboundAnalogue:ANPUnboundUnboundUnbound
1jqhC01UnboundAnalogue:ANPUnboundUnboundUnbound
1k3aA01UnboundAnalogue:ACPBound:G-E-Y-V-N-I-E-F(chain B)UnboundUnbound
1m7nA01UnboundUnboundUnboundUnboundUnbound
1m7nB01UnboundUnboundUnboundUnboundUnbound
1p4oA01UnboundUnboundUnboundUnboundUnbound
1p4oB01UnboundUnboundUnboundUnboundUnbound
1jqhA02UnboundUnboundUnboundUnboundUnbound
1jqhB02UnboundUnboundUnboundUnboundUnbound
1jqhC02UnboundUnboundUnboundUnboundUnbound
1k3aA02UnboundUnboundUnboundUnboundUnbound
1m7nA02UnboundUnboundUnboundUnboundUnbound
1m7nB02UnboundUnboundUnboundUnboundUnbound
1p4oA02UnboundUnboundUnboundUnboundUnbound
1p4oB02UnboundUnboundUnboundUnboundUnbound

Active-site residues
pdbCatalytic residuesModified residues
          
1igrA01 
 
1igrA02 
 
1igrA03 
 
1jqhA01 
 
1jqhB01 
 
1jqhC01 
 
1k3aA01 
 
1m7nA01 
 
1m7nB01 
 
1p4oA01 
 
1p4oB01 
 
1jqhA02ASP 1135;ARG 1139
        ;TYR 1165;TYR 1166(auto-phosphorylation)
1jqhB02ASP 1135;ARG 1139
        ;TYR 1165;TYR 1166(auto-phosphorylation)
1jqhC02ASP 1135;ARG 1139
        ;TYR 1165;TYR 1166(auto-phosphorylation)
1k3aA02ASP 1105;ARG 1109
PTR 1131;PTR 1135;PTR 1136(auto-phosphorylation)
1m7nA02ASP 1132;ARG 1136
TYR 1158;TYR 1162;TYR 1163(auto-phosphorylation)
1m7nB02ASP 1132;ARG 1136
TYR 1158;TYR 1162;TYR 1163(auto-phosphorylation)
1p4oA02ASP 1105;ARG 1109
TYR 1131;TYR 1135;TYR 1136(auto-phosphorylation)
1p4oB02ASP 1105;ARG 1109
TYR 1131;TYR 1135;TYR 1136(auto-phosphorylation)

References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[17]p.10061
[19]p.959

references
[1]
PubMed ID7514345
JournalAdv Exp Med Biol
Year1993
Volume343
Pages33-40
AuthorsCascieri MA, Bayne ML
TitleAnalysis of the interaction of IGF-I analogs with the IGF-I receptor and IGF binding proteins.
[2]
PubMed ID7868068
JournalHorm Res
Year1994
Volume42
Pages152-69
AuthorsDe Meyts P, Wallach B, Christoffersen CT, Urso B, Gronskov K, Latus LJ, Yakushiji F, Ilondo MM, Shymko RM
TitleThe insulin-like growth factor-I receptor. Structure, ligand-binding mechanism and signal transduction.
[3]
PubMed ID9202243
JournalEndocrinology
Year1997
Volume138
Pages2979-88
AuthorsEsposito DL, Blakesley VA, Koval AP, Scrimgeour AG, LeRoith D
TitleTyrosine residues in the C-terminal domain of the insulin-like growth factor-I receptor mediate mitogenic and tumorigenic signals.
[4]
PubMed ID9416620
JournalProtein Sci
Year1997
Volume6
Pages2663-6
AuthorsMcKern NM, Lou M, Frenkel MJ, Verkuylen A, Bentley JD, Lovrecz GO, Ivancic N, Elleman TC, Garrett TP, Cosgrove LJ, Ward CW
TitleCrystallization of the first three domains of the human insulin-like growth factor-1 receptor.
[5]
CommentsX-ray crystallography
PubMed ID9690478
JournalNature
Year1998
Volume394
Pages395-9
AuthorsGarrett TP, McKern NM, Lou M, Frenkel MJ, Bentley JD, Lovrecz GO, Elleman TC, Cosgrove LJ, Ward CW
TitleCrystal structure of the first three domains of the type-1 insulin-like growth factor receptor.
Related PDB1igr
[6]
PubMed ID10026153
JournalJ Biol Chem
Year1999
Volume274
Pages5422-8
AuthorsArbet-Engels C, Tartare-Deckert S, Eckhart W
TitleC-terminal Src kinase associates with ligand-stimulated insulin-like growth factor-I receptor.
[7]
PubMed ID11162456
JournalBiochem Biophys Res Commun
Year2000
Volume279
Pages955-60
AuthorsLopaczynski W, Terry C, Nissley P
TitleAutophosphorylation of the insulin-like growth factor I receptor cytoplasmic domain.
[8]
PubMed ID10816097
JournalBiochem Soc Trans
Year2000
Volume28
Pages47-51
AuthorsO'Connor R, Fennelly C, Krause D
TitleRegulation of survival signals from the insulin-like growth factor-I receptor.
[9]
PubMed ID11162597
JournalBiochem Biophys Res Commun
Year2001
Volume280
Pages836-41
AuthorsMaggi D, Cordera R
TitleCys 786 and Cys 776 in the posttranslational processing of the insulin and IGF-I receptors.
[10]
PubMed ID11498020
JournalBiochem Soc Trans
Year2001
Volume29
Pages513-25
AuthorsSiddle K, Urso B, Niesler CA, Cope DL, Molina L, Surinya KH, Soos MA
TitleSpecificity in ligand binding and intracellular signalling by insulin and insulin-like growth factor receptors.
[11]
PubMed ID11714281
JournalBiochemistry
Year2001
Volume40
Pages14268-78
AuthorsBaer K, Al-Hasani H, Parvaresch S, Corona T, Rufer A, Nolle V, Bergschneider E, Klein HW
TitleDimerization-induced activation of soluble insulin/IGF-1 receptor kinases: an alternative mechanism of activation.
[12]
PubMed ID11737239
JournalEur J Clin Invest
Year2001
Volume31
Pages966-77
AuthorsVan Obberghen E, Baron V, Delahaye L, Emanuelli B, Filippa N, Giorgetti-Peraldi S, Lebrun P, Mothe-Satney I, Peraldi P, Rocchi S, Sawka-Verhelle D, Tartare-Deckert S, Giudicelli J
TitleSurfing the insulin signaling web.
[13]
PubMed ID11445579
JournalJ Biol Chem
Year2001
Volume276
Pages33419-27
AuthorsLigensa T, Krauss S, Demuth D, Schumacher R, Camonis J, Jaques G, Weidner KM
TitleA PDZ domain protein interacts with the C-terminal tail of the insulin-like growth factor-1 receptor but not with the insulin receptor.
[14]
PubMed ID11445567
JournalJ Biol Chem
Year2001
Volume276
Pages33608-15
AuthorsBrodt P, Fallavollita L, Khatib AM, Samani AA, Zhang D
TitleCooperative regulation of the invasive and metastatic phenotypes by different domains of the type I insulin-like growth factor receptor beta subunit.
[15]
PubMed ID11500492
JournalJ Biol Chem
Year2001
Volume276
Pages43980-6
AuthorsWhittaker J, Groth AV, Mynarcik DC, Pluzek L, Gadsboll VL, Whittaker LJ
TitleAlanine scanning mutagenesis of a type 1 insulin-like growth factor receptor ligand binding site.
[16]
PubMed ID11376122
JournalMol Pathol
Year2001
Volume54
Pages125-32
AuthorsWard CW, Garrett TP, McKern NM, Lou M, Cosgrove LJ, Sparrow LG, Frenkel MJ, Hoyne PA, Elleman TC, Adams TE, Lovrecz GO, Lawrence LJ, Tulloch PA
TitleThe three dimensional structure of the type I insulin-like growth factor receptor.
[17]
PubMed ID11694888
JournalNat Struct Biol
Year2001
Volume8
Pages1058-63
AuthorsFavelyukis S, Till JH, Hubbard SR, Miller WT
TitleStructure and autoregulation of the insulin-like growth factor 1 receptor kinase.
Related PDB1k3a
[18]
PubMed ID11287679
JournalProtein Eng
Year2001
Volume14
Pages61-5
AuthorsGeddes S, Holst P, Grotzinger J, Gill R, Nugent P, De Meyts P, Wollmer A, Wood S, Pitts J
TitleStructure-function studies of an IGF-I analogue that can be chemically cleaved to a two-chain mini-IGF-I.
[19]
PubMed ID11591350
JournalStructure (Camb)
Year2001
Volume9
Pages955-65
AuthorsPautsch A, Zoephel A, Ahorn H, Spevak W, Hauptmann R, Nar H
TitleCrystal structure of bisphosphorylated IGF-1 receptor kinase: insight into domain movements upon kinase activation.
Related PDB1jqh
[20]
PubMed ID12138114
JournalJ Biol Chem
Year2002
Volume277
Pages38797-802
AuthorsMunshi S, Kornienko M, Hall DL, Reid JC, Waxman L, Stirdivant SM, Darke PL, Kuo LC
TitleCrystal structure of the Apo, unactivated insulin-like growth factor-1 receptor kinase. Implication for inhibitor specificity.
Related PDB1m7n,1p4o

comments
The E.C. was transferred from 2.7.1.112 to 2.7.10.1.
This protein is a receptor enzyme, insulin-like growth factor I receptor, composed of two chains, alpha and beta. PDB structure, 1igr, corresponds to the N-terminal domains of the alpha chain. The beta chain is composed of an extracellular reagion, transmembrane region, and a cytoplasmic region. The extracellular region contains a fibronectin type-III domain, whilst the cytoplasmic region has got a kinase domain. PDB structures, 1jqh, 1k3a, 1m7n & 1p4o, correspond to the kinase domain.
According to the literature [17] & [19], Asp1105 (of PDB entry 1k3a) seemes to be a general base, which can activate the acceptor group, the hydroxyl group of substrate tyrosine, which in turn would make a nucleophilic attack on the transferred group, gamma-phosphate group of ATP. Arg1109 also seems to interact with both the general base and the acceptor hydroxyl group. Although two magnesium ions are coordinated to the beta- and gamma-phosphates of ATP analogue in a homologous receptor enzyme, Insulin receptor kinase (see M00129), only one magnesium ion is coordinated by the alpha- and gamma-phosphates and two water molecules (see [19]).

createdupdated
2004-03-302009-02-26


Copyright: Nozomi Nagano, JST & CBRC-AIST
Funded by PRESTO/Japan Science and Technology Corporation (JST) (December 2001 - November 2004)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2006)
Funded by Grant-in-Aid for Scientific Research (B)/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (September 2005 - September 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (October 2007 - September 2010)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2011 - March 2012)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2012 - March 2013)
Supported by the commission for the Development of Artificial Gene Synthesis Technology for Creating Innovative Biomaterial from the Ministry of Economy, Trade and Industry (METI) (October 2012 - )
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