DB code: M00124

RLCP classification 3.103.130000.1162 : Transfer
CATH domain 2.60.120.260 : Jelly Rolls
-.-.-.- :
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
1.10.150.50 : DNA polymerase; domain 1
E.C. 2.7.10.1
CSA
M-CSA
MACiE

CATH domain Related DB codes (homologues)
1.10.510.10 : Transferase(Phosphotransferase); domain 1 M00125 M00131 T00224 M00127 M00129 M00130 M00132 M00136 M00196 M00197 M00198 M00304 M00323 M00325 M00326 M00327 M00328 M00329 M00330 M00331 M00332 M00333 M00335 M00339 M00344
2.60.120.260 : Jelly Rolls T00005 T00065 T00066
2.60.40.30 : Immunoglobulin-like M00134 M00129 M00136 M00149 M00192
3.30.200.20 : Phosphorylase Kinase; domain 1 M00125 M00131 T00224 M00127 M00129 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 Pfam RefSeq
P54763 Ephrin type-B receptor 2
EC 2.7.10.1
Tyrosine-protein kinase receptor EPH-3
Neural kinase
Nuk receptor tyrosine kinase
SEK-3
PF01404 (Ephrin_lbd)
PF00041 (fn3)
PF07699 (GCC2_GCC3)
PF07714 (Pkinase_Tyr)
PF00536 (SAM_1)
[Graphical View]
P28693 Ephrin type-B receptor 2
EC 2.7.10.1
Tyrosine-protein kinase receptor CEK5
PF01404 (Ephrin_lbd)
PF00041 (fn3)
PF07699 (GCC2_GCC3)
PF07714 (Pkinase_Tyr)
PF00536 (SAM_1)
[Graphical View]
NP_996834.1 (Protein)
NM_206951.3 (DNA/RNA sequence)

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
P54763 EPHB2_MOUSE ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate. Interacts with PRKCABP. The ligand-activated form interacts with multiple proteins, including GTPase-activating protein (RASGAP) through its SH2 domain. Binds RASGAP through the juxtamembrane tyrosines residues (By similarity). Interacts with PRKCABP and GRIP1. Membrane, Single-pass type I membrane protein.
P28693 EPHB2_CHICK ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate. 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
15422
16761
PubChem 888
5957
6022
1nukA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
1kgyA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
1kgyB Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
1kgyC Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
1kgyD Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
1jpaA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Analogue:ANP Unbound
1jpaB01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Analogue:ANP Unbound
1jpaA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
1jpaB02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
1sggA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound

Reference for Active-site residues
resource references E.C.
Swiss-prot & Similarity with M00129

Active-site residues
PDB Catalytic residues Cofactor-binding residues Modified residues Main-chain involved in catalysis Comment
1nukA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
1kgyA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
1kgyB Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
1kgyC Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
1kgyD Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
1jpaA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain mutant Y604F, Y610F
1jpaB01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain mutant Y604F, Y610F
1jpaA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 754;ARG 758 ASN 759;ASP 772(Magnesium binding)
1jpaB02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 754;ARG 758 ASN 759;ASP 772(Magnesium binding)
1sggA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain TYR 25 (Phospholylated)

References for Catalytic Mechanism
References Sections No. of steps in catalysis
[9]
[10]

References
[1]
Resource
Comments
Medline ID
PubMed ID 9233798
Journal EMBO J
Year 1997
Volume 16
Pages 3877-88
Authors Holland SJ, Gale NW, Gish GD, Roth RA, Songyang Z, Cantley LC, Henkemeyer M, Yancopoulos GD, Pawson T
Title Juxtamembrane tyrosine residues couple the Eph family receptor EphB2/Nuk to specific SH2 domain proteins in neuronal cells.
Related PDB
Related UniProtKB
[2]
Resource
Comments X-ray crystallography
Medline ID
PubMed ID 9853759
Journal Nature
Year 1998
Volume 396
Pages 486-91
Authors Himanen JP, Henkemeyer M, Nikolov DB
Title Crystal structure of the ligand-binding domain of the receptor tyrosine kinase EphB2.
Related PDB 1nuk
Related UniProtKB
[3]
Resource
Comments INTERACTION WITH PRKCABP
Medline ID 99098206
PubMed ID 9883737
Journal Neuron
Year 1998
Volume 21
Pages 1453-63
Authors Torres R, Firestein BL, Dong H, Staudinger J, Olson EN, Huganir RL, Bredt DS, Gale NW, Yancopoulos GD
Title PDZ proteins bind, cluster, and synaptically colocalize with Eph receptors and their ephrin ligands.
Related PDB
Related UniProtKB P54763
[4]
Resource
Comments
Medline ID
PubMed ID 9632142
Journal Oncogene
Year 1998
Volume 16
Pages 2657-70
Authors Zisch AH, Kalo MS, Chong LD, Pasquale EB
Title Complex formation between EphB2 and Src requires phosphorylation of tyrosine 611 in the EphB2 juxtamembrane region.
Related PDB
Related UniProtKB
[5]
Resource
Comments
Medline ID
PubMed ID 10523848
Journal Oncogene
Year 1999
Volume 18
Pages 5680-90
Authors Yoshii S, Tanaka M, Otsuki Y, Wang DY, Guo RJ, Zhu Y, Takeda R, Hanai H, Kaneko E, Sugimura H
Title alphaPIX nucleotide exchange factor is activated by interaction with phosphatidylinositol 3-kinase.
Related PDB
Related UniProtKB
[6]
Resource
Comments
Medline ID
PubMed ID 10555534
Journal Cell Tissue Res
Year 1999
Volume 298
Pages 1-9
Authors Kalo MS, Pasquale EB
Title Signal transfer by Eph receptors.
Related PDB
Related UniProtKB
[7]
Resource
Comments
Medline ID
PubMed ID 10356296
Journal Mol Cell Neurosci
Year 1999
Volume 13
Pages 337-47
Authors Scully AL, McKeown M, Thomas JB
Title Isolation and characterization of Dek, a Drosophila eph receptor protein tyrosine kinase.
Related PDB
Related UniProtKB
[8]
Resource
Comments
Medline ID
PubMed ID 10449409
Journal EMBO J
Year 1999
Volume 18
Pages 4438-45
Authors Chi SW, Ayed A, Arrowsmith CH
Title Solution structure of a conserved C-terminal domain of p73 with structural homology to the SAM domain.
Related PDB
Related UniProtKB
[9]
Resource
Comments
Medline ID
PubMed ID 9886291
Journal Nat Struct Biol
Year 1999
Volume 6
Pages 44-9
Authors Stapleton D, Balan I, Pawson T, Sicheri F
Title The crystal structure of an Eph receptor SAM domain reveals a mechanism for modular dimerization.
Related PDB
Related UniProtKB
[10]
Resource
Comments NMR Structures
Medline ID
PubMed ID 10548040
Journal Protein Sci
Year 1999
Volume 8
Pages 1954-61
Authors Smalla M, Schmieder P, Kelly M, Ter Laak A, Krause G, Ball L, Wahl M, Bork P, Oschkinat H
Title Solution structure of the receptor tyrosine kinase EphB2 SAM domain and identification of two distinct homotypic interaction sites.
Related PDB 1sgg
Related UniProtKB
[11]
Resource
Comments
Medline ID
PubMed ID 9933164
Journal Science
Year 1999
Volume 283
Pages 833-6
Authors Thanos CD, Goodwill KE, Bowie JU
Title Oligomeric structure of the human EphB2 receptor SAM domain.
Related PDB
Related UniProtKB
[12]
Resource
Comments
Medline ID
PubMed ID 10848605
Journal Mol Cell Biol
Year 2000
Volume 20
Pages 4791-805
Authors Binns KL, Taylor PP, Sicheri F, Pawson T, Holland SJ
Title Phosphorylation of tyrosine residues in the kinase domain and juxtamembrane region regulates the biological and catalytic activities of Eph receptors.
Related PDB
Related UniProtKB
[13]
Resource
Comments FUNCTION
Medline ID 20171264
PubMed ID 10704386
Journal Development
Year 2000
Volume 127
Pages 1397-410
Authors Imondi R, Wideman C, Kaprielian Z
Title Complementary expression of transmembrane ephrins and their receptors in the mouse spinal cord: a possible role in constraining the orientation of longitudinally projecting axons.
Related PDB
Related UniProtKB P54763
[14]
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 1jpa
Related UniProtKB
[15]
Resource
Comments
Medline ID
PubMed ID 11780069
Journal Nature
Year 2001
Volume 414
Pages 933-8
Authors Himanen JP, Rajashankar KR, Lackmann M, Cowan CA, Henkemeyer M, Nikolov DB
Title Crystal structure of an Eph receptor-ephrin complex.
Related PDB 1kgy
Related UniProtKB
[16]
Resource
Comments
Medline ID
PubMed ID 11718293
Journal Eur Biophys J
Year 2001
Volume 30
Pages 411-5
Authors Behlke J, Labudde D, Ristau O
Title Self-association studies on the EphB2 receptor SAM domain using analytical ultracentrifugation.
Related PDB
Related UniProtKB
[17]
Resource
Comments
Medline ID
PubMed ID 12054873
Journal J Mol Biol
Year 2002
Volume 319
Pages 823-37
Authors Baldisseri DM, Margolis JW, Weber DJ, Koo JH, Margolis FL
Title Olfactory marker protein (OMP) exhibits a beta-clam fold in solution: implications for target peptide interaction and olfactory signal transduction.
Related PDB
Related UniProtKB
[18]
Resource
Comments
Medline ID
PubMed ID 12054872
Journal J Mol Biol
Year 2002
Volume 319
Pages 807-21
Authors Smith PC, Firestein S, Hunt JF
Title The crystal structure of the olfactory marker protein at 2.3 A resolution.
Related PDB
Related UniProtKB
[19]
Resource
Comments
Medline ID
PubMed ID 12141423
Journal Int J Dev Biol
Year 2002
Volume 46
Pages 375-84
Authors Coulthard MG, Duffy S, Down M, Evans B, Power M, Smith F, Stylianou C, Kleikamp S, Oates A, Lackmann M, Burns GF, Boyd AW
Title The role of the Eph-ephrin signalling system in the regulation of developmental patterning.
Related PDB
Related UniProtKB
[20]
Resource
Comments
Medline ID
PubMed ID 12528767
Journal Eur J Cancer
Year 2002
Volume 38 Suppl 5
Pages S3-10
Authors Pawson T
Title Regulation and targets of receptor tyrosine kinases.
Related PDB
Related UniProtKB
[21]
Resource
Comments
Medline ID
PubMed ID 12100883
Journal Curr Opin Genet Dev
Year 2002
Volume 12
Pages 397-402
Authors Drescher U
Title Eph family functions from an evolutionary perspective.
Related PDB
Related UniProtKB

Comments
The E.C. was transferred from 2.7.1.112 to 2.7.10.1.
The Eph receptor tyrosine kinase family is regulated by autophosphorylation within the juxtamembrane region and the kinase activation segment. This receptor enzyme has N-terminal extracellular region, which is composed of ligand-binding domain, Cys-rich domain, and two fibronectine type-III domain, transmembrane region, and cytoplasmic region, which is composed of juxtamembrane region, protein kinase domain, and SAM domain.
PDB structures, 1nuk & 1kgy, correspond to the first domain of this enzyme, ligand-binding domain, the other structure, 1jpa, comprises the fifth domain, juxtamembrane region, and the sixth domain, protein kinase domain. PDB structure, 1sgg, corresponds to the last domain, SAM. However, tertiary structures of the rest of domains, the second domain, Cys-rich domain, the third and fourth domains, two fibronectin type-III domains, have not been determined yet.
The last domain is sterile alpha motif (SAM) domain, which was found in various signaling proteins such as tyrosine and serine/threonine protein kinases, regulators of lipid metabolism, and GTPases, according to the literature [9]. The SAM domain is involved in protein-protein interaction, rather than catalysis, through the ability to oligomerize with other SAM domains [9].
This SAM domain has a conserved tyrosine (Tyr25, PDB;1sgg), which was reported to be essential for the interaction with SH2 domains after its phosphorylation (see paper [10]).
Although the tertiary structure of the catalytic domain has been determined, its catalytic mechanism is still unclear. However, since the structure is homologous to other kinase domains with complete conservation of active site residues, the mechanism can be similar to those ones (see M00129).

Created Updated
2003-07-22 2009-02-26