DB code: M00129

RLCP classification 3.103.130000.1162 : Transfer
CATH domain -.-.-.- :
2.60.40.30 : Immunoglobulin-like
2.60.40.30 : Immunoglobulin-like
3.30.200.20 : Phosphorylase Kinase; domain 1
1.10.510.10 : Transferase(Phosphotransferase); domain 1 Catalytic domain
-.-.-.- :
E.C. 2.7.10.1
CSA 1ir3
M-CSA 1ir3
MACiE M0246

CATH domain Related DB codes (homologues)
1.10.510.10 : Transferase(Phosphotransferase); domain 1 M00125 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-like M00124 M00134 M00136 M00149 M00192
3.30.200.20 : Phosphorylase Kinase; domain 1 M00125 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

Uniprot Enzyme Name
UniprotKB Protein name Synonyms Contains RefSeq Pfam
P06213 Insulin receptor (IR) (EC 2.7.10.1)AltName: CD_antigen=CD220;
None Insulin receptor subunit alpha
Insulin receptor subunit beta
NP_000199.2 (Protein)
NM_000208.2 (DNA/RNA sequence)
NP_001073285.1 (Protein)
NM_001079817.1 (DNA/RNA sequence)
PF00041 (fn3)
PF00757 (Furin-like)
PF07714 (Pkinase_Tyr)
PF01030 (Recep_L_domain)
[Graphical View]

KEGG enzyme name
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

UniprotKB: Accession Number Entry name Activity Subunit Subcellular location Cofactor
P06213 INSR_HUMAN ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate. Tetramer 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. Membrane, Single-pass type I membrane protein.

KEGG Pathways
Map code Pathways E.C.

Compound table
Cofactors Substrates Products Intermediates
KEGG-id C00305 C00002 C00585 C00008 C01167
E.C.
Compound magnesium ATP [Protein]-L-tyrosine ADP [Protein]-L-tyrosine phosphate
Type divalent metal (Ca2+, Mg2+) amine group,nucleotide aromatic ring (only carbon atom),peptide/protein amine group,nucleotide aromatic ring (only carbon atom),peptide/protein,phosphate group/phosphate ion
ChEBI 18420
 18420
 		15422
 15422
 		16761
 16761
PubChem 888
 888
 		5957
 5957
 		6022
 6022
1gagA01 Unbound Analogue:112 Unbound Unbound Unbound
1i44A01 Unbound Analogue:ACP Unbound Unbound Unbound
1ir3A01 Unbound Analogue:ANP Unbound Unbound Unbound
1irkA01 Unbound Unbound Unbound Unbound Unbound
1gagA02 Bound:2x_MG Unbound Analogue:PHE_107(chain B) Unbound Unbound
1i44A02 Bound:_MG Unbound Unbound Unbound Unbound
1ir3A02 Bound:2x_MG Unbound Bound:GLY-ASP-TYR-MET-ASN-MET(chain B) Unbound Unbound
1irkA02 Unbound Unbound Unbound Unbound Unbound

Reference for Active-site residues
resource references E.C.
Swiss-prot; P00520, P00519, P41240, P08631, P06239, P00523, P12931

Active-site residues
PDB Catalytic residues Cofactor-binding residues Modified residues Main-chain involved in catalysis Comment
1gagA01
1i44A01
1ir3A01 mutant C981S;Y984F
1irkA01 mutant C981S;Y984F
1gagA02 ASP 1132;ARG 1136 ASN 1137;ASP 1150(Magnesium binding) PTR 1158;PTR 1162;PTR 1163(auto-phosphorylation)
1i44A02 ASP 1132;ARG 1136 ASN 1137;ASP 1150(Magnesium binding) invisible 1155-1170
1ir3A02 ASP 1132;ARG 1136 ASN 1137;ASP 1150(Magnesium binding) PTR 1158;PTR 1162;PTR 1163(auto-phosphorylation)
1irkA02 ASP 1132;ARG 1136 ASN 1137;ASP 1150(Magnesium binding) TYR 1158;TYR 1162;TYR 1163(auto-phosphorylation)

References for Catalytic Mechanism
References Sections No. 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]
Resource
Comments AUTOPHOSPHORYLATION.
Medline ID 92337603
PubMed ID 1321605
Journal Biochem Biophys Res Commun
Year 1992
Volume 186
Pages 244-50
Authors Dickens M, Tavare JM
Title Analysis of the order of autophosphorylation of human insulin receptor tyrosines 1158, 1162 and 1163.
Related PDB
Related UniProtKB P06213
[2]
Resource
Comments
Medline ID
PubMed ID 7528141
Journal Eur J Biochem
Year 1994
Volume 226
Pages 525-36
Authors Keane NE, Chavanieu A, Quirk PG, Evans JS, Levine BA, Calas B, Wei L, Ellis L
Title Structural determinants of substrate selection by the human insulin-receptor protein-tyrosine kinase.
Related PDB
Related UniProtKB
[3]
Resource
Comments X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 1005-1310.
Medline ID 95089813
PubMed ID 7997262
Journal Nature
Year 1994
Volume 372
Pages 746-54
Authors Hubbard SR, Wei L, Ellis L, Hendrickson WA
Title Crystal structure of the tyrosine kinase domain of the human insulin receptor.
Related PDB 1irk
Related UniProtKB P06213
[4]
Resource
Comments
Medline ID
PubMed ID 7713916
Journal J Biol Chem
Year 1995
Volume 270
Pages 8122-30
Authors Wei L, Hubbard SR, Hendrickson WA, Ellis L
Title Expression, characterization, and crystallization of the catalytic core of the human insulin receptor protein-tyrosine kinase domain.
Related PDB
Related UniProtKB
[5]
Resource
Comments X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 1005-1310.
Medline ID 97459943
PubMed ID 9312016
Journal EMBO J
Year 1997
Volume 16
Pages 5572-81
Authors Hubbard SR
Title Crystal structure of the activated insulin receptor tyrosine kinase in complex with peptide substrate and ATP analog.
Related PDB 1ir3
Related UniProtKB P06213
[6]
Resource
Comments
Medline ID
PubMed ID 10074361
Journal Biochemistry
Year 1999
Volume 38
Pages 3079-89
Authors Bishop SM, Ross JB, Kohanski RA
Title Autophosphorylation dependent destabilization of the insulin receptor kinase domain: tryptophan-1175 reports changes in the catalytic cleft.
Related PDB
Related UniProtKB
[7]
Resource
Comments
Medline ID
PubMed ID 10869355
Journal J Biol Chem
Year 2000
Volume 275
Pages 30394-8
Authors Ablooglu AJ, Till JH, Kim K, Parang K, Cole PA, Hubbard SR, Kohanski RA
Title Probing the catalytic mechanism of the insulin receptor kinase with a tetrafluorotyrosine-containing peptide substrate.
Related PDB
Related UniProtKB
[8]
Resource
Comments
Medline ID
PubMed ID 11148045
Journal Biochemistry
Year 2001
Volume 40
Pages 504-13
Authors Ablooglu AJ, Kohanski RA
Title Activation of the insulin receptor's kinase domain changes the rate-determining step of substrate phosphorylation.
Related PDB
Related UniProtKB
[9]
Resource
Comments X-ray crystallography
Medline ID
PubMed ID 11124964
Journal J Biol Chem
Year 2001
Volume 276
Pages 10049-55
Authors Till JH, Ablooglu AJ, Frankel M, Bishop SM, Kohanski RA, Hubbard SR
Title Crystallographic and solution studies of an activation loop mutant of the insulin receptor tyrosine kinase: insights into kinase mechanism.
Related PDB 1i44
Related UniProtKB
[10]
Resource
Comments X-ray crystallography
Medline ID
PubMed ID 11135668
Journal Nat Struct Biol
Year 2001
Volume 8
Pages 37-41
Authors Parang K, Till JH, Ablooglu AJ, Kohanski RA, Hubbard SR, Cole PA
Title Mechanism-based design of a protein kinase inhibitor.
Related PDB 1gag
Related UniProtKB
[11]
Resource
Comments
Medline ID
PubMed ID 11572780
Journal Cell
Year 2001
Volume 106
Pages 745-57
Authors Wybenga-Groot LE, Baskin B, Ong SH, Tong J, Pawson T, Sicheri F
Title Structural basis for autoinhibition of the Ephb2 receptor tyrosine kinase by the unphosphorylated juxtamembrane region.
Related PDB
Related UniProtKB

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.

Created Updated
2004-03-03 2009-02-26