EzCatDB: M00129
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DB codeM00129
RLCP classification3.103.130000.1162 : Transfer
CATH domainDomain 1-.-.-.-
Domain 22.60.40.30 : Immunoglobulin-like
Domain 32.60.40.30 : Immunoglobulin-like
Domain 43.30.200.20 : Phosphorylase Kinase; domain 1
Domain 51.10.510.10 : Transferase(Phosphotransferase); domain 1Catalytic domain
Domain 6-.-.-.-
E.C.2.7.10.1
CSA1ir3
MACiEM0246

CATH domainRelated DB codes (homologues)
1.10.510.10 : Transferase(Phosphotransferase); domain 1M00125,M00124,M00131,T00224,M00127,M00130,M00132,M00136,M00196,M00197,M00198,M00304,M00323,M00325,M00326,M00327,M00328,M00329,M00330,M00331,M00332,M00333,M00335,M00339,M00344
2.60.40.30 : Immunoglobulin-likeM00124,M00134,M00136,M00149,M00192
3.30.200.20 : Phosphorylase Kinase; domain 1M00125,M00124,M00131,T00224,M00127,M00130,M00132,M00136,M00196,M00197,M00198,M00304,M00323,M00325,M00326,M00327,M00328,M00329,M00330,M00331,M00332,M00333,M00335,M00339,M00344,D00298

Enzyme Name
UniProtKBKEGG

P06213
Protein nameInsulin receptor (IR) (EC 2.7.10.1)AltName: CD_antigen=CD220;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 receptor subunit alpha
Insulin receptor subunit beta
RefSeqNP_000199.2 (Protein)
NM_000208.2 (DNA/RNA sequence)
NP_001073285.1 (Protein)
NM_001079817.1 (DNA/RNA sequence)
PfamPF00041 (fn3)
PF00757 (Furin-like)
PF07714 (Pkinase_Tyr)
PF01030 (Recep_L_domain)
[Graphical view]


UniProtKB:Accession NumberP06213
Entry nameINSR_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 chains carry the kinase domain. Interacts with SORBS1 but dissociates from it following insulin stimulation. Binds SH2B2. Interacts with the PTB/PID domains of IRS1 and SHC1 in vitro when autophosphorylated on tyrosine residues. The sequences surrounding the phosphorylated NPXY motif contribute differentially to either IRS1 or SHC1 recognition. Interacts with the SH2 domains of the 85 kDa regulatory subunit of PI3K (PIK3R1) in vitro, when autophosphorylated on tyrosine residues. Interacts with SOCS7.
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

             
1gagA01UnboundAnalogue:112UnboundUnboundUnbound
1i44A01UnboundAnalogue:ACPUnboundUnboundUnbound
1ir3A01UnboundAnalogue:ANPUnboundUnboundUnbound
1irkA01UnboundUnboundUnboundUnboundUnbound
1gagA02Bound:2x_MGUnboundAnalogue:PHE 107(chain B)UnboundUnbound
1i44A02Bound:_MGUnboundUnboundUnboundUnbound
1ir3A02Bound:2x_MGUnboundBound:GLY-ASP-TYR-MET-ASN-MET(chain B)UnboundUnbound
1irkA02UnboundUnboundUnboundUnboundUnbound

Active-site residues
resource
Swiss-prot; P00520, P00519, P41240, P08631, P06239, P00523, P12931
pdbCatalytic residuesCofactor-binding residuesModified residuescomment
            
1gagA01 
 
 
 
1i44A01 
 
 
 
1ir3A01 
 
 
mutant C981S;Y984F
1irkA01 
 
 
mutant C981S;Y984F
1gagA02ASP 1132;ARG 1136
ASN 1137;ASP 1150(Magnesium binding)
PTR 1158;PTR 1162;PTR 1163(auto-phosphorylation)
 
1i44A02ASP 1132;ARG 1136
ASN 1137;ASP 1150(Magnesium binding)
                                                
invisible 1155-1170
1ir3A02ASP 1132;ARG 1136
ASN 1137;ASP 1150(Magnesium binding)
PTR 1158;PTR 1162;PTR 1163(auto-phosphorylation)
 
1irkA02ASP 1132;ARG 1136
ASN 1137;ASP 1150(Magnesium binding)
TYR 1158;TYR 1162;TYR 1163(auto-phosphorylation)
 

References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[3]p.750-752
[5]p.5578-5579
[7]p.30396-30398, Fig.1
[10]Fig.1, p.37

references
[1]
CommentsAUTOPHOSPHORYLATION.
Medline ID92337603
PubMed ID1321605
JournalBiochem Biophys Res Commun
Year1992
Volume186
Pages244-50
AuthorsDickens M, Tavare JM
TitleAnalysis of the order of autophosphorylation of human insulin receptor tyrosines 1158, 1162 and 1163.
Related UniProtKBP06213
[2]
PubMed ID7528141
JournalEur J Biochem
Year1994
Volume226
Pages525-36
AuthorsKeane NE, Chavanieu A, Quirk PG, Evans JS, Levine BA, Calas B, Wei L, Ellis L
TitleStructural determinants of substrate selection by the human insulin-receptor protein-tyrosine kinase.
[3]
CommentsX-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 1005-1310.
Medline ID95089813
PubMed ID7997262
JournalNature
Year1994
Volume372
Pages746-54
AuthorsHubbard SR, Wei L, Ellis L, Hendrickson WA
TitleCrystal structure of the tyrosine kinase domain of the human insulin receptor.
Related PDB1irk
Related UniProtKBP06213
[4]
PubMed ID7713916
JournalJ Biol Chem
Year1995
Volume270
Pages8122-30
AuthorsWei L, Hubbard SR, Hendrickson WA, Ellis L
TitleExpression, characterization, and crystallization of the catalytic core of the human insulin receptor protein-tyrosine kinase domain.
[5]
CommentsX-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 1005-1310.
Medline ID97459943
PubMed ID9312016
JournalEMBO J
Year1997
Volume16
Pages5572-81
AuthorsHubbard SR
TitleCrystal structure of the activated insulin receptor tyrosine kinase in complex with peptide substrate and ATP analog.
Related PDB1ir3
Related UniProtKBP06213
[6]
PubMed ID10074361
JournalBiochemistry
Year1999
Volume38
Pages3079-89
AuthorsBishop SM, Ross JB, Kohanski RA
TitleAutophosphorylation dependent destabilization of the insulin receptor kinase domain: tryptophan-1175 reports changes in the catalytic cleft.
[7]
PubMed ID10869355
JournalJ Biol Chem
Year2000
Volume275
Pages30394-8
AuthorsAblooglu AJ, Till JH, Kim K, Parang K, Cole PA, Hubbard SR, Kohanski RA
TitleProbing the catalytic mechanism of the insulin receptor kinase with a tetrafluorotyrosine-containing peptide substrate.
[8]
PubMed ID11148045
JournalBiochemistry
Year2001
Volume40
Pages504-13
AuthorsAblooglu AJ, Kohanski RA
TitleActivation of the insulin receptor's kinase domain changes the rate-determining step of substrate phosphorylation.
[9]
CommentsX-ray crystallography
PubMed ID11124964
JournalJ Biol Chem
Year2001
Volume276
Pages10049-55
AuthorsTill JH, Ablooglu AJ, Frankel M, Bishop SM, Kohanski RA, Hubbard SR
TitleCrystallographic and solution studies of an activation loop mutant of the insulin receptor tyrosine kinase: insights into kinase mechanism.
Related PDB1i44
[10]
CommentsX-ray crystallography
PubMed ID11135668
JournalNat Struct Biol
Year2001
Volume8
Pages37-41
AuthorsParang K, Till JH, Ablooglu AJ, Kohanski RA, Hubbard SR, Cole PA
TitleMechanism-based design of a protein kinase inhibitor.
Related PDB1gag
[11]
PubMed ID11572780
JournalCell
Year2001
Volume106
Pages745-57
AuthorsWybenga-Groot LE, Baskin B, Ong SH, Tong J, Pawson T, Sicheri F
TitleStructural basis for autoinhibition of the Ephb2 receptor tyrosine kinase by the unphosphorylated juxtamembrane region.

comments
The E.C. was transferred from 2.7.1.112 to 2.7.10.1.
This receptor enzyme has N-terminal extracellular region, transmembrane region, and C-terminal cytoplasmic region. Whilst the extracellular region is composed of Cys-rich domain, and two fibronectin type-III domains, the cytoplasmic region contains a protein kinase domain.
According to the literature [5], the carboxylate group of Asp1132 is hydrogen-bonded to the hydroxyl group of the substrate tyrosine, so that proton removal from the hydroxyl group of the tyrosine by the general base, Asp1132, can occur. However, the gamma-phosphorus atom of ATP analogue is 5.0 A from the hydroxyl oxygen of the tyrosine, which is not position for associative (SN2) phosphotransfer mechanism. On the other hand, papers [7] and [10] suggested that the catalysis proceeds via dissociative (SN1) mechanism. According to the paper [7], the pKa of the hydroxyl group of substrate tyrosine is elevated so that it is protonated during the transition state, which supports a dissociative mechanism. Moreover, the paper [10] suggested that the distance between the transferred gamma-phosphate and the acceptor tyrosine hydroxyl oxygen atom favors a dissociative mechanism. According to the literature [10], the importance of the nucleophilicity of the attacking hydroxyl group is diminished and departure of the leaving group (ADP) is well advanced. Thus, the gamma-phosphoryl group moves toward the entering oxygen, and the nucleophile and the ADP are fixed during the transition state. Furthermore, proton abstraction from the hydroxyl group of the substrate tyrosine by the general base, Asp1132, occurs late in the dissociative mechanism.
Meanwhile, two magnesium ions are bound to the active site. The first Mg2+ is cooridnated by oxygen atoms from the beta- and gamma-phosphates, oxygens from sidechains of Asn1137 and Asp1150, and two oxygen atoms from water molecules. The second Mg2+ is coordinated by oxygen from beta-phosphate, both carboxylate oxygens of Asp1150, and four water molecules. Those magnesium ions might be inhibitory or activating, compared with other kinases.

createdupdated
2004-03-032009-02-26


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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)
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