M00326
type: Enzyme
rlcp: p1162
cath: http://ezcatdb.cbrc.jp/EzCatDB/cath/2.60.-.-
cath: Immunoglobulin-like
cath: http://ezcatdb.cbrc.jp/EzCatDB/cath/-.-.-.-
cath: Phosphorylase Kinase; domain 1
cath: Transferase(Phosphotransferase); domain 1
ec: https://purl.uniprot.org/enzyme/2.7.10.1
uniprot: P07949
kegg enzyme: Receptor protein-tyrosine kinase
kegg enzyme: ATP:protein-tyrosine O-phosphotransferase (ambiguous)
kegg enzyme: Protein-tyrosine kinase (ambiguous)
kegg enzyme: Protein tyrosine kinase (ambiguous)
kegg enzyme: Receptor protein tyrosine kinase
kegg enzyme: RET
kegg cofactor: Mg
kegg substrate: ATP
kegg substrate: [protein]-L-tyrosine
kegg product: ADP
kegg product: [protein]-L-tyrosine phosphate
pdb: 2x2uA01
pdb: 2x2uA02
pdb: 2ivsA01
pdb: 2ivsB01
pdb: 2ivtA01
pdb: 2ivuA01
pdb: 2ivvA01
pdb: 2x2kA01
pdb: 2x2lA01
pdb: 2x2mA01
pdb: 2x2mB01
pdb: 2ivsA02
pdb: 2ivsB02
pdb: 2ivtA02
pdb: 2ivuA02
pdb: 2ivvA02
pdb: 2x2kA02
pdb: 2x2lA02
pdb: 2x2mA02
pdb: 2x2mB02
pdb bound state: Unbound
  compound: ATP
  pdb: 2x2uA01
pdb bound state: Unbound
  compound: ATP
  pdb: 2x2uA02
pdb bound state: Unbound
  compound: ATP
  pdb: 2ivsA01
pdb bound state: Unbound
  compound: ATP
  pdb: 2ivsB01
pdb bound state: Unbound
  compound: ATP
  pdb: 2ivtA01
pdb bound state: Unbound
  compound: ATP
  pdb: 2ivuA01
pdb bound state: Unbound
  compound: ATP
  pdb: 2ivvA01
pdb bound state: Unbound
  compound: ATP
  pdb: 2x2kA01
pdb bound state: Unbound
  compound: ATP
  pdb: 2x2lA01
pdb bound state: Unbound
  compound: ATP
  pdb: 2x2mA01
pdb bound state: Unbound
  compound: ATP
  pdb: 2x2mB01
pdb bound state: Unbound
  compound: ATP
  pdb: 2ivsA02
pdb bound state: Unbound
  compound: ATP
  pdb: 2ivsB02
pdb bound state: Unbound
  compound: ATP
  pdb: 2ivtA02
pdb bound state: Unbound
  compound: ATP
  pdb: 2ivuA02
pdb bound state: Unbound
  compound: ATP
  pdb: 2ivvA02
pdb bound state: Unbound
  compound: ATP
  pdb: 2x2kA02
pdb bound state: Unbound
  compound: ATP
  pdb: 2x2lA02
pdb bound state: Unbound
  compound: ATP
  pdb: 2x2mA02
pdb bound state: Unbound
  compound: ATP
  pdb: 2x2mB02
pdb bound state: Unbound
  compound: [protein]-L-tyrosine
  pdb: 2x2uA01
active site residues resources: P07949
references: GDNF-induced activation of the ret protein tyrosine kinase is mediated by GDNFR-alpha, a novel receptor for GDNF.
references: Characterization of a multicomponent receptor for GDNF.
references: A GPI-linked protein that interacts with Ret to form a candidate neurturin receptor.
references: Calcium-dependent Ret activation by GDNF and neurturin.
references: Distinct structural elements in GDNF mediate binding to GFRalpha1 and activation of the GFRalpha1-c-Ret receptor complex.
references: Molecular modeling of the extracellular domain of the RET receptor tyrosine kinase reveals multiple cadherin-like domains and a calcium-binding site.
references: The GDNF family: signalling, biological functions and therapeutic value.
references: Identification of a surface for binding to the GDNF-GFR alpha 1 complex in the first cadherin-like domain of RET.
references: The structure of GFRalpha1 domain 3 reveals new insights into GDNF binding and RET activation.
references: Direct interactions among Ret, GDNF and GFRalpha1 molecules reveal new insights into the assembly of a functional three-protein complex.
references: Structure and chemical inhibition of the RET tyrosine kinase domain.
references: Quantitative analysis of the activation mechanism of the multicomponent growth-factor receptor Ret.
references: Structure of artemin complexed with its receptor GFRalpha3: convergent recognition of glial cell line-derived neurotrophic factors.
references: GDNF family receptor complexes are emerging drug targets.
references: The structure of the glial cell line-derived neurotrophic factor-coreceptor complex: insights into RET signaling and heparin binding.
references: Synthesis, structure-activity relationship and crystallographic studies of 3-substituted indolin-2-one RET inhibitors.
references: Mammal-restricted elements predispose human RET to folding impairment by HSCR mutations.
comment: This enzyme belongs to receptor tyrosine kinase family. This enzyme consists of the N-terminal extracellular region, the transmembrane region, and the C-terminal intracellular region (see [7] and [11]). The extracellular region is composed of four N-terminal cadherin-like domains followed by a cysteine-rich domain (see [6], [7] and [11]). On the other hand, the intracellular region is composed of a juxtamembrane domain, a kinase domain, and a tail region (see [7] and [11]). The catalytic domain of this enzyme is homologous to that of vascular endothelial growth factor receptor (M00131 in EzCatDB). According to the literature [7], [8], [10] and [11], this enzyme is activated by binding to a complex of a glial cell line-derived neutrophic factor (GDNF) family ligand and its cognate receptor, the GDNF family receptor alpha (GFRalpha). The GDNF family ligands, including GDNF, neurturin (NRTN), artemin (ARTN) and persephin (PSPN), are homologous to the transforming growth factor-beta (TGF-beta) (see [7]). GFRalpha1 binds preferentially to GDNF, GFRalpha2 to NRTN, GFRalpha3 to ARTN, and GFRalpha4 to PSPN (see [7] and [13]). These receptor complexes with this enzyme can be drug targets (see [14]). According to the literature[11], autophosphorylation of Tyr905 on A-loop is not required for RET catalytic activity.

Immunoglobulin-like
type: Cath
references: http://www.cathdb.info/version/latest/superfamily/2.60.40.60

Phosphorylase Kinase; domain 1
type: Cath
references: http://www.cathdb.info/version/latest/superfamily/3.30.200.20

Transferase(Phosphotransferase); domain 1
type: Cath
references: http://www.cathdb.info/version/latest/superfamily/1.10.510.10
catalytic domain: index.html

Mg
type: KeggCofactor
references: KEGG:C00305
compound type: divalent metal (Ca2+, Mg2+)
references: CHEBI:18420
references: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi

ATP
type: KeggSubstrate
references: KEGG:C00002
compound type: amine group
compound type: nucleotide
references: CHEBI:15422
references: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi

[protein]-L-tyrosine
type: KeggSubstrate
references: KEGG:C00585
compound type: aromatic ring (only carbon atom)
compound type: peptide/protein

ADP
type: KeggProduct
references: KEGG:C00008
compound type: amine group
compound type: nucleotide
references: CHEBI:16761
references: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi

[protein]-L-tyrosine phosphate
type: KeggProduct
references: KEGG:C01167
compound type: aromatic ring (only carbon atom)
compound type: peptide/protein
compound type: phosphate group/phosphate ion

2ivtA01
type: Pdb
references: 2ivt
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:2ivt
comment: invisible 712-714

2ivuA01
type: Pdb
references: 2ivu
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:2ivu
comment: invisible 713

2ivvA01
type: Pdb
references: 2ivv
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:2ivv
comment: invisible 712-715

2x2kA01
type: Pdb
references: 2x2k
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:2x2k
comment: invisible 712-714

2x2lA01
type: Pdb
references: 2x2l
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:2x2l
comment: invisible 713-714

2x2mA01
type: Pdb
references: 2x2m
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:2x2m
comment: invisible 713

2x2mB01
type: Pdb
references: 2x2m
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:2x2m
comment: invisible 712-714

2ivsA02
type: Pdb
references: 2ivs
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:2ivs
catalytic residue: ASP 874;ARG 878
cofactor binding residue: ASN 879;ASP 892 (Magnesium binding)
modified residue: TYR 905 (auto-phosphorylation)
comment: invisible 828-843

2ivsB02
type: Pdb
references: 2ivs
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:2ivs
catalytic residue: ASP 874;ARG 878
cofactor binding residue: ASN 879;ASP 892 (Magnesium binding)
modified residue: (auto-phosphorylation)
comment: invisible 822-843, 900-910

2ivtA02
type: Pdb
references: 2ivt
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:2ivt
catalytic residue: ASP 874;ARG 878
cofactor binding residue: ASN 879;ASP 892 (Magnesium binding)
modified residue: PTR 905 (auto-phosphorylation)
comment: invisible 823-843

2ivuA02
type: Pdb
references: 2ivu
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:2ivu
catalytic residue: ASP 874;ARG 878
cofactor binding residue: ASN 879;ASP 892 (Magnesium binding)
modified residue: PTR 905 (auto-phosphorylation)
comment: invisible 821-843

2ivvA02
type: Pdb
references: 2ivv
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:2ivv
catalytic residue: ASP 874;ARG 878
cofactor binding residue: ASN 879;ASP 892 (Magnesium binding)
modified residue: PTR 905 (auto-phosphorylation)
comment: invisible 821-845

2x2kA02
type: Pdb
references: 2x2k
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:2x2k
catalytic residue: ASP 874;ARG 878
cofactor binding residue: ASN 879;ASP 892 (Magnesium binding)
modified residue: PTR 905 (auto-phosphorylation)
comment: invisible 823-843

2x2lA02
type: Pdb
references: 2x2l
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:2x2l
catalytic residue: ASP 874;ARG 878
cofactor binding residue: ASN 879;ASP 892 (Magnesium binding)
modified residue: PTR 905 (auto-phosphorylation)
comment: invisible 823-843

2x2mA02
type: Pdb
references: 2x2m
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:2x2m
catalytic residue: ASP 874;ARG 878
cofactor binding residue: ASN 879;ASP 892 (Magnesium binding)
modified residue: PTR 905 (auto-phosphorylation)
comment: invisible 821-844

2x2mB02
type: Pdb
references: 2x2m
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:2x2m
catalytic residue: ASP 874;ARG 878
cofactor binding residue: ASN 879;ASP 892 (Magnesium binding)
modified residue: PTR 905 (auto-phosphorylation)
comment: invisible 820-844

GDNF-induced activation of the ret protein tyrosine kinase is mediated by GDNFR-alpha, a novel receptor for GDNF.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/8674117
journal: Cell
volume: 85
pages: 1113-24
published year: 1996
authors:
  item: Jing S
  item: Wen D
  item: Yu Y
  item: Holst PL
  item: Luo Y
  item: Fang M
  item: Tamir R
  item: Antonio L
  item: Hu Z
  item: Cupples R
  item: Louis JC
  item: Hu S
  item: Altrock BW
  item: Fox GM

Characterization of a multicomponent receptor for GDNF.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/8657309
journal: Nature
volume: 382
pages: 80-3
published year: 1996
authors:
  item: Treanor JJ
  item: Goodman L
  item: de Sauvage F
  item: Stone DM
  item: Poulsen KT
  item: Beck CD
  item: Gray C
  item: Armanini MP
  item: Pollock RA
  item: Hefti F
  item: Phillips HS
  item: Goddard A
  item: Moore MW
  item: Buj-Bello A
  item: Davies AM
  item: Asai N
  item: Takahashi M
  item: Vandlen R
  item: Henderson CE
  item: Rosenthal A

A GPI-linked protein that interacts with Ret to form a candidate neurturin receptor.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/9192898
journal: Nature
volume: 387
pages: 717-21
published year: 1997
authors:
  item: Klein RD
  item: Sherman D
  item: Ho WH
  item: Stone D
  item: Bennett GL
  item: Moffat B
  item: Vandlen R
  item: Simmons L
  item: Gu Q
  item: Hongo JA
  item: Devaux B
  item: Poulsen K
  item: Armanini M
  item: Nozaki C
  item: Asai N
  item: Goddard A
  item: Phillips H
  item: Henderson CE
  item: Takahashi M
  item: Rosenthal A

Calcium-dependent Ret activation by GDNF and neurturin.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/9467954
journal: Oncogene
volume: 16
pages: 293-9
published year: 1998
authors:
  item: Nozaki C
  item: Asai N
  item: Murakami H
  item: Iwashita T
  item: Iwata Y
  item: Horibe K
  item: Klein RD
  item: Rosenthal A
  item: Takahashi M

Distinct structural elements in GDNF mediate binding to GFRalpha1 and activation of the GFRalpha1-c-Ret receptor complex.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/10545102
journal: EMBO J
volume: 18
pages: 5901-10
published year: 1999
authors:
  item: Eketjall S
  item: Fainzilber M
  item: Murray-Rust J
  item: Ibanez CF

Molecular modeling of the extracellular domain of the RET receptor tyrosine kinase reveals multiple cadherin-like domains and a calcium-binding site.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/11445581
journal: J Biol Chem
volume: 276
pages: 35808-17
published year: 2001
authors:
  item: Anders J
  item: Kjar S
  item: Ibanez CF

The GDNF family: signalling, biological functions and therapeutic value.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/11988777
journal: Nat Rev Neurosci
volume: 3
pages: 383-94
published year: 2002
authors:
  item: Airaksinen MS
  item: Saarma M

Identification of a surface for binding to the GDNF-GFR alpha 1 complex in the first cadherin-like domain of RET.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/14514671
journal: J Biol Chem
volume: 278
pages: 47898-904
published year: 2003
authors:
  item: Kjaer S
  item: Ibanez CF

The structure of GFRalpha1 domain 3 reveals new insights into GDNF binding and RET activation.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/15044950
journal: EMBO J
volume: 23
pages: 1452-62
published year: 2004
authors:
  item: Leppanen VM
  item: Bespalov MM
  item: Runeberg-Roos P
  item: Puurand U
  item: Merits A
  item: Saarma M
  item: Goldman A

Direct interactions among Ret, GDNF and GFRalpha1 molecules reveal new insights into the assembly of a functional three-protein complex.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/15722196
journal: Cell Signal
volume: 17
pages: 717-27
published year: 2005
authors:
  item: Amoresano A
  item: Incoronato M
  item: Monti G
  item: Pucci P
  item: de Franciscis V
  item: Cerchia L

Structure and chemical inhibition of the RET tyrosine kinase domain.
type: BibliographicResource
comment: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 705-1013 ALONE AND IN COMPLEX WITH INHIBITORS, MASS SPECTROMETRY, PHOSPHORYLATION AT TYR-900 AND TYR-905.
references: http://www.ncbi.nlm.nih.gov/pubmed/16928683
journal: J Biol Chem
volume: 281
pages: 33577-87
published year: 2006
authors:
  item: Knowles PP
  item: Murray-Rust J
  item: Kjaer S
  item: Scott RP
  item: Hanrahan S
  item: Santoro M
  item: Ibanez CF
  item: McDonald NQ
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: P07949

Quantitative analysis of the activation mechanism of the multicomponent growth-factor receptor Ret.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/17013378
journal: Nat Chem Biol
volume: 2
pages: 636-44
published year: 2006
authors:
  item: Schlee S
  item: Carmillo P
  item: Whitty A

Structure of artemin complexed with its receptor GFRalpha3: convergent recognition of glial cell line-derived neurotrophic factors.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/16765900
journal: Structure
volume: 14
pages: 1083-92
published year: 2006
authors:
  item: Wang X
  item: Baloh RH
  item: Milbrandt J
  item: Garcia KC

GDNF family receptor complexes are emerging drug targets.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/17218019
journal: Trends Pharmacol Sci
volume: 28
pages: 68-74
published year: 2007
authors:
  item: Bespalov MM
  item: Saarma M

The structure of the glial cell line-derived neurotrophic factor-coreceptor complex: insights into RET signaling and heparin binding.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/18845535
journal: J Biol Chem
volume: 283
pages: 35164-72
published year: 2008
authors:
  item: Parkash V
  item: Leppanen VM
  item: Virtanen H
  item: Jurvansuu JM
  item: Bespalov MM
  item: Sidorova YA
  item: Runeberg-Roos P
  item: Saarma M
  item: Goldman A

Synthesis, structure-activity relationship and crystallographic studies of 3-substituted indolin-2-one RET inhibitors.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/20117004
journal: Bioorg Med Chem
volume: 18
pages: 1482-96
published year: 2010
authors:
  item: Mologni L
  item: Rostagno R
  item: Brussolo S
  item: Knowles PP
  item: Kjaer S
  item: Murray-Rust J
  item: Rosso E
  item: Zambon A
  item: Scapozza L
  item: McDonald NQ
  item: Lucchini V
  item: Gambacorti-Passerini C
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: P07949

Mammal-restricted elements predispose human RET to folding impairment by HSCR mutations.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/20473317
journal: Nat Struct Mol Biol
volume: 17
pages: 726-31
published year: 2010
authors:
  item: Kjaer S
  item: Hanrahan S
  item: Totty N
  item: McDonald NQ
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: P07949

Analogue
compound: ADP
pdb: 2ivsA01
ligand het code: ACK

Analogue
compound: ADP
pdb: 2ivsB01
ligand het code: ACK

Analogue
compound: ADP
pdb: 2ivtA01
ligand het code: AMP

ReferenceForCatalyticMechanism
reference index: 12
reference section: Figure 5