DB code: M00328

RLCP classification 3.103.130000.1162 : Transfer
CATH domain -.-.-.- :
2.60.120.- : Jelly Rolls
2.60.120.- : Jelly Rolls
-.-.-.- :
-.-.-.- :
-.-.-.- :
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
M-CSA
MACiE

CATH domain Related DB codes (homologues)
1.10.510.10 : Transferase(Phosphotransferase); domain 1 M00125 M00124 M00131 T00224 M00127 M00129 M00130 M00132 M00136 M00196 M00197 M00198 M00304 M00323 M00325 M00326 M00327 M00329 M00330 M00331 M00332 M00333 M00335 M00339 M00344
3.30.200.20 : Phosphorylase Kinase; domain 1 M00125 M00124 M00131 T00224 M00127 M00129 M00130 M00132 M00136 M00196 M00197 M00198 M00304 M00323 M00325 M00326 M00327 M00329 M00330 M00331 M00332 M00333 M00335 M00339 M00344 D00298

Uniprot Enzyme Name
UniprotKB Protein name Synonyms RefSeq Pfam
Q9UM73 ALK tyrosine kinase receptor (EC 2.7.10.1) (Anaplastic lymphoma kinase)AltName: CD_antigen=CD246;
None NP_004295.2 (Protein)
NM_004304.4 (DNA/RNA sequence)
PF00629 (MAM)
PF07714 (Pkinase_Tyr)
[Graphical View]

KEGG enzyme name
Receptor protein-tyrosine kinase
ALK
Anaplastic lymphoma kinase
ATP:protein-tyrosine O-phosphotransferase (ambiguous)
Protein-tyrosine kinase (ambiguous)
Protein tyrosine kinase (ambiguous)
Receptor protein tyrosine kinase

UniprotKB: Accession Number Entry name Activity Subunit Subcellular location Cofactor
Q9UM73 ALK_HUMAN ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate. Homodimer. Homodimerizes when bound to ligand. Interacts with FRS2, IRS1, MDK, PTN and SHC1. Interacts with CBL, PIK3R1 and PLCG1 (By similarity). Cell membrane, Single-pass type I membrane protein. Note=Membrane attachment was crucial for promotion of neuron-like differentiation and cell proliferation arrest through specific activation of the MAP kinase pathway.

KEGG Pathways
Map code Pathways E.C.

Compound table
Cofactors Substrates Products Intermediates
KEGG-id C00305 C00002 C00585 C00008 C01167
E.C.
Compound Mg 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
2xb7A01 Unbound Unbound Unbound Unbound Unbound
2xbaA01 Unbound Unbound Unbound Unbound Unbound
2xp2A01 Unbound Unbound Unbound Unbound Unbound
2yfxA01 Unbound Unbound Unbound Unbound Unbound
2yhvA01 Unbound Unbound Unbound Unbound Unbound
2yjrA01 Unbound Unbound Unbound Unbound Unbound
2yjsA01 Unbound Unbound Unbound Unbound Unbound
3aoxA01 Unbound Unbound Unbound Unbound Unbound
3l9pA01 Unbound Unbound Unbound Unbound Unbound
3lcsA01 Unbound Unbound Unbound Unbound Unbound
3lctA01 Unbound Unbound Unbound Bound:ADP Unbound
4dceA01 Unbound Unbound Unbound Unbound Unbound
4dceB01 Unbound Unbound Unbound Unbound Unbound
4fnwA01 Unbound Unbound Unbound Unbound Unbound
4fnxA01 Unbound Unbound Unbound Unbound Unbound
4fnyA01 Unbound Unbound Unbound Unbound Unbound
4fnzA01 Unbound Unbound Unbound Unbound Unbound
4fobA01 Unbound Unbound Unbound Unbound Unbound
4focA01 Unbound Unbound Unbound Unbound Unbound
4fodA01 Unbound Unbound Unbound Unbound Unbound
2xb7A02 Unbound Unbound Unbound Unbound Unbound
2xbaA02 Unbound Unbound Unbound Unbound Unbound
2xp2A02 Unbound Unbound Unbound Unbound Unbound
2yfxA02 Unbound Unbound Unbound Unbound Unbound
2yhvA02 Unbound Unbound Unbound Unbound Unbound
2yjrA02 Unbound Unbound Unbound Unbound Unbound
2yjsA02 Unbound Unbound Unbound Unbound Unbound
3aoxA02 Unbound Unbound Unbound Unbound Unbound
3l9pA02 Unbound Unbound Unbound Unbound Unbound
3lcsA02 Unbound Unbound Unbound Unbound Unbound
3lctA02 Unbound Unbound Unbound Unbound Unbound
4dceA02 Unbound Unbound Unbound Unbound Unbound
4dceB02 Unbound Unbound Unbound Unbound Unbound
4fnwA02 Unbound Unbound Unbound Unbound Unbound
4fnxA02 Unbound Unbound Unbound Unbound Unbound
4fnyA02 Unbound Unbound Unbound Unbound Unbound
4fnzA02 Unbound Unbound Unbound Unbound Unbound
4fobA02 Unbound Unbound Unbound Unbound Unbound
4focA02 Unbound Unbound Unbound Unbound Unbound
4fodA02 Unbound Unbound Unbound Unbound Unbound
2kupB Unbound Unbound Unbound Unbound Unbound
2ys5B Unbound Unbound Unbound Unbound Unbound

Reference for Active-site residues
resource references E.C.
Literature [5] & Swiss-prot;Q9UM73

Active-site residues
PDB Catalytic residues Cofactor-binding residues Modified residues Main-chain involved in catalysis Comment
2xb7A01 invisible 1137-1143
2xbaA01 invisible 1123-1129, 1137-1143
2xp2A01 invisible 1124-1125, 1137-1143
2yfxA01 invisible 1124-1125, 1136-1143
2yhvA01 invisible 1123-1125, 1136-1143
2yjrA01 invisible 1137-1143
2yjsA01 invisible 1125-1128, 1137-1143
3aoxA01 invisible 1124-1127, 1137-1143
3l9pA01 invisible 1138-1142
3lcsA01
3lctA01
4dceA01 invisible 1125-1127, 1137-1141
4dceB01 invisible 1125-1128, 1137-1142
4fnwA01 invisible 1124-1127, 1137-1142
4fnxA01 invisible 1123-1128, 1137-1141
4fnyA01 invisible 1125-1127, 1138-1143
4fnzA01 invisible 1125-1127, 1138-1142
4fobA01 invisible 1137-1142
4focA01 invisible 1137-1142
4fodA01 invisible 1137-1142
2xb7A02 ASP 1249;ARG 1253 ASN 1254;ASP 1270(Magnesium binding) invisible 1275-1288
2xbaA02 ASP 1249;ARG 1253 ASN 1254;ASP 1270(Magnesium binding) TYR 1278(auto-phosphorylation) invisible 1279-1288
2xp2A02 ASP 1249;ARG 1253 ASN 1254;ASP 1270(Magnesium binding) TYR 1278(auto-phosphorylation) invisible 1281-1289
2yfxA02 ASP 1249;ARG 1253 ASN 1254;ASP 1270(Magnesium binding) TYR 1278(auto-phosphorylation) invisible 1280-1285
2yhvA02 ASP 1249;ARG 1253 ASN 1254;ASP 1270(Magnesium binding) TYR 1278(auto-phosphorylation) invisible 1280-1285
2yjrA02 ASP 1249;ARG 1253 ASN 1254;ASP 1270(Magnesium binding) invisible 1274-1287
2yjsA02 ASP 1249;ARG 1253 ASN 1254;ASP 1270(Magnesium binding) TYR 1278(auto-phosphorylation) invisible 1280-1287
3aoxA02 ASP 1249;ARG 1253 ASN 1254;ASP 1270(Magnesium binding) TYR 1278(auto-phosphorylation) invisible 1281-1287
3l9pA02 ASP 1249;ARG 1253 ASN 1254;ASP 1270(Magnesium binding) TYR 1278(auto-phosphorylation)
3lcsA02 ASP 1249;ARG 1253 ASN 1254;ASP 1270(Magnesium binding) TYR 1278(auto-phosphorylation)
3lctA02 ASP 1249;ARG 1253 ASN 1254;ASP 1270(Magnesium binding) TYR 1278(auto-phosphorylation)
4dceA02 ASP 1249;ARG 1253 ASN 1254;ASP 1270(Magnesium binding) invisible 1273-1286
4dceB02 ASP 1249;ARG 1253 ASN 1254;ASP 1270(Magnesium binding) invisible 1273-1287
4fnwA02 ASP 1249;ARG 1253 ASN 1254;ASP 1270(Magnesium binding) TYR 1278(auto-phosphorylation) invisible 1280-1287
4fnxA02 ASP 1249;ARG 1253 ASN 1254;ASP 1270(Magnesium binding) TYR 1278(auto-phosphorylation) invisible 1279-1287
4fnyA02 ASP 1249;ARG 1253 ASN 1254;ASP 1270(Magnesium binding) invisible 1216-1219, 1272-1287
4fnzA02 ASP 1249;ARG 1253 ASN 1254;ASP 1270(Magnesium binding) invisible 1273-1287
4fobA02 ASP 1249;ARG 1253 ASN 1254;ASP 1270(Magnesium binding) TYR 1278(auto-phosphorylation) invisible 1216-1218, 1281-1286
4focA02 ASP 1249;ARG 1253 ASN 1254;ASP 1270(Magnesium binding) TYR 1278(auto-phosphorylation) invisible 1280-1287
4fodA02 ASP 1249;ARG 1253 ASN 1254;ASP 1270(Magnesium binding) TYR 1278(auto-phosphorylation) invisible 1281-1287
2kupB
2ys5B

References for Catalytic Mechanism
References Sections No. of steps in catalysis

References
[1]
Resource
Comments INTERACTION WITH PTN, FUNCTION.
Medline ID
PubMed ID 11278720
Journal J Biol Chem
Year 2001
Volume 276
Pages 16772-9
Authors Stoica GE, Kuo A, Aigner A, Sunitha I, Souttou B, Malerczyk C, Caughey DJ, Wen D, Karavanov A, Riegel AT, Wellstein A
Title Identification of anaplastic lymphoma kinase as a receptor for the growth factor pleiotrophin.
Related PDB
Related UniProtKB
[2]
Resource
Comments INTERACTION WITH MDK, FUNCTION.
Medline ID
PubMed ID 12122009
Journal J Biol Chem
Year 2002
Volume 277
Pages 35990-8
Authors Stoica GE, Kuo A, Powers C, Bowden ET, Sale EB, Riegel AT, Wellstein A
Title Midkine binds to anaplastic lymphoma kinase (ALK) and acts as a growth factor for different cell types.
Related PDB
Related UniProtKB
[3]
Resource
Comments SUBSTRATE SPECIFICITY.
Medline ID
PubMed ID 15938644
Journal Biochemistry
Year 2005
Volume 44
Pages 8533-42
Authors Tartari CJ, Mologni L, Scapozza L, Gambacorti-Passerini C, Pinna LA
Title Unique substrate specificity of anaplastic lymphoma kinase (ALK): development of phosphoacceptor peptides for the assay of ALK activity.
Related PDB
Related UniProtKB
[4]
Resource
Comments
Medline ID
PubMed ID 18070884
Journal J Biol Chem
Year 2008
Volume 283
Pages 3743-50
Authors Tartari CJ, Gunby RH, Coluccia AM, Sottocornola R, Cimbro B, Scapozza L, Donella-Deana A, Pinna LA, Gambacorti-Passerini C
Title Characterization of some molecular mechanisms governing autoactivation of the catalytic domain of the anaplastic lymphoma kinase.
Related PDB
Related UniProtKB
[5]
Resource
Comments X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 1072-1410.
Medline ID
PubMed ID 20632993
Journal Biochem J
Year 2010
Volume 430
Pages 425-37
Authors Lee CC, Jia Y, Li N, Sun X, Ng K, Ambing E, Gao MY, Hua S, Chen C, Kim S, Michellys PY, Lesley SA, Harris JL, Spraggon G
Title Crystal structure of the ALK (anaplastic lymphoma kinase) catalytic domain.
Related PDB 3l9p 3lcs 3lct
Related UniProtKB Q9UM73
[6]
Resource
Comments X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF 1094-1407 IN COMPLEX WITH INHIBITOR.
Medline ID
PubMed ID 20695522
Journal Biochemistry
Year 2010
Volume 49
Pages 6813-25
Authors Bossi RT, Saccardo MB, Ardini E, Menichincheri M, Rusconi L, Magnaghi P, Orsini P, Avanzi N, Borgia AL, Nesi M, Bandiera T, Fogliatto G, Bertrand JA
Title Crystal structures of anaplastic lymphoma kinase in complex with ATP competitive inhibitors.
Related PDB 2xb7 2xba
Related UniProtKB Q9UM73
[7]
Resource
Comments
Medline ID
PubMed ID 20454865
Journal J Struct Funct Genomics
Year 2010
Volume 11
Pages 125-41
Authors Koshiba S, Li H, Motoda Y, Tomizawa T, Kasai T, Tochio N, Yabuki T, Harada T, Watanabe S, Tanaka A, Shirouzu M, Kigawa T, Yamamoto T, Yokoyama S
Title Structural basis for the recognition of nucleophosmin-anaplastic lymphoma kinase oncoprotein by the phosphotyrosine binding domain of Suc1-associated neurotrophic factor-induced tyrosine-phosphorylated target-2.
Related PDB 2kup 2ys5
Related UniProtKB
[8]
Resource
Comments X-RAY CRYSTALLOGRAPHY (1.75 ANGSTROMS) OF 1069-1411 IN COMPLEX WITH INHIBITOR, ENZYME REGULATION.
Medline ID
PubMed ID 21575866
Journal Cancer Cell
Year 2011
Volume 19
Pages 679-90
Authors Sakamoto H, Tsukaguchi T, Hiroshima S, Kodama T, Kobayashi T, Fukami TA, Oikawa N, Tsukuda T, Ishii N, Aoki Y
Title CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant.
Related PDB 3aox
Related UniProtKB Q9UM73
[9]
Resource
Comments
Medline ID
PubMed ID 21812414
Journal J Med Chem
Year 2011
Volume 54
Pages 6342-6363
Authors Cui JJ, Tran-Dube? M, Shen H, Nambu M, Kung PP, Pairish M, Jia L, Meng J, Funk L, Botrous I, McTigue M, Grodsky N, Ryan K, Padrique E, Alton G, Timofeevski S, Yamazaki S, Li Q, Zou H, Christensen J, Mroczkowski B, Bender S, Kania RS, Edwards MP
Title Structure Based Drug Design of Crizotinib (PF-02341066), a Potent and Selective Dual Inhibitor of Mesenchymal-Epithelial Transition Factor (c-MET) Kinase and Anaplastic Lymphoma Kinase (ALK).
Related PDB 2xp2
Related UniProtKB Q9UM73
[10]
Resource
Comments
Medline ID
PubMed ID 22263917
Journal J Med Chem
Year 2012
Volume 55
Pages 1698-705
Authors Bryan MC, Whittington DA, Doherty EM, Falsey JR, Cheng AC, Emkey R, Brake RL, Lewis RT
Title Rapid development of piperidine carboxamides as potent and selective anaplastic lymphoma kinase inhibitors.
Related PDB 4dce
Related UniProtKB
[11]
Resource
Comments
Medline ID
PubMed ID 22734674
Journal J Med Chem
Year 2012
Volume 55
Pages 6523-40
Authors Lewis RT, Bode CM, Choquette DM, Potashman M, Romero K, Stellwagen JC, Teffera Y, Moore E, Whittington DA, Chen H, Epstein LF, Emkey R, Andrews PS, Yu VL, Saffran DC, Xu M, Drew A, Merkel P, Szilvassy S, Brake RL
Title The discovery and optimization of a novel class of potent, selective, and orally bioavailable anaplastic lymphoma kinase (ALK) inhibitors with potential utility for the treatment of cancer.
Related PDB 4fob 4foc 4fod
Related UniProtKB
[12]
Resource
Comments
Medline ID
PubMed ID 22932897
Journal J Biol Chem
Year 2012
Volume 287
Pages 37447-57
Authors Epstein LF, Chen H, Emkey R, Whittington DA
Title The R1275Q neuroblastoma mutant and certain ATP-competitive inhibitors stabilize alternative activation loop conformations of anaplastic lymphoma kinase.
Related PDB 4fnw 4fnx 4fny 4fnz
Related UniProtKB

Comments
This enzyme is a receptor for growth factors, pleiotrophin (UniProt; P21246) and midkine (UniProt; P21741), which are homologous to each other (see [1] and [2]).
This enzyme belongs to the insulin receptor kinase superfamily (see [5]).
This enzyme consists of the N-terminal extracellular region, the transmembrane region and the C-terminal cytoplasmic region (see [5]). The extracellular region is composed of an N-terminal region, whose structure has not been elucidated yet, two MAM domains, low-density lipoprotein class A (LDL-A) domain, and a glycine-rich region (see [5]). The cytoplasmic region is composed of a juxtamembrane region, a catalytic domain and a C-terminal region (see [5]).
The catalytic domain is homologous to that of insulin receptor kinase (M00129 in EzCatDB).

Created Updated
2011-11-04 2013-01-17