EzCatDB: M00328
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DB codeM00328
RLCP classification3.103.130000.1162 : Transfer
CATH domainDomain 1-.-.-.-
Domain 22.60.120.- : Jelly Rolls
Domain 32.60.120.- : Jelly Rolls
Domain 4-.-.-.-
Domain 5-.-.-.-
Domain 6-.-.-.-
Domain 73.30.200.20 : Phosphorylase Kinase; domain 1
Domain 81.10.510.10 : Transferase(Phosphotransferase); domain 1Catalytic domain
Domain 9-.-.-.-
E.C.2.7.10.1

CATH domainRelated DB codes (homologues)
1.10.510.10 : Transferase(Phosphotransferase); domain 1M00125,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 1M00125,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

Enzyme Name
UniProtKBKEGG

Q9UM73
Protein nameALK tyrosine kinase receptor (EC 2.7.10.1) (Anaplastic lymphoma kinase)AltName: CD_antigen=CD246;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
SynonymsNone
RefSeqNP_004295.2 (Protein)
NM_004304.4 (DNA/RNA sequence)
PfamPF00629 (MAM)
PF07714 (Pkinase_Tyr)
[Graphical view]


UniProtKB:Accession NumberQ9UM73
Entry nameALK_HUMAN
ActivityATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
SubunitHomodimer. Homodimerizes when bound to ligand. Interacts with FRS2, IRS1, MDK, PTN and SHC1. Interacts with CBL, PIK3R1 and PLCG1 (By similarity).
Subcellular locationCell 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.
Cofactor

Compound table: links to PDB-related databases & PoSSuM

CofactorsSubstratesProducts
KEGG-idC00305C00002C00585C00008C01167
CompoundMgATP[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

             
2xb7A01UnboundUnboundUnboundUnboundUnbound
2xbaA01UnboundUnboundUnboundUnboundUnbound
2xp2A01UnboundUnboundUnboundUnboundUnbound
2yfxA01UnboundUnboundUnboundUnboundUnbound
2yhvA01UnboundUnboundUnboundUnboundUnbound
2yjrA01UnboundUnboundUnboundUnboundUnbound
2yjsA01UnboundUnboundUnboundUnboundUnbound
3aoxA01UnboundUnboundUnboundUnboundUnbound
3l9pA01UnboundUnboundUnboundUnboundUnbound
3lcsA01UnboundUnboundUnboundUnboundUnbound
3lctA01UnboundUnboundUnboundBound:ADPUnbound
4dceA01UnboundUnboundUnboundUnboundUnbound
4dceB01UnboundUnboundUnboundUnboundUnbound
4fnwA01UnboundUnboundUnboundUnboundUnbound
4fnxA01UnboundUnboundUnboundUnboundUnbound
4fnyA01UnboundUnboundUnboundUnboundUnbound
4fnzA01UnboundUnboundUnboundUnboundUnbound
4fobA01UnboundUnboundUnboundUnboundUnbound
4focA01UnboundUnboundUnboundUnboundUnbound
4fodA01UnboundUnboundUnboundUnboundUnbound
2xb7A02UnboundUnboundUnboundUnboundUnbound
2xbaA02UnboundUnboundUnboundUnboundUnbound
2xp2A02UnboundUnboundUnboundUnboundUnbound
2yfxA02UnboundUnboundUnboundUnboundUnbound
2yhvA02UnboundUnboundUnboundUnboundUnbound
2yjrA02UnboundUnboundUnboundUnboundUnbound
2yjsA02UnboundUnboundUnboundUnboundUnbound
3aoxA02UnboundUnboundUnboundUnboundUnbound
3l9pA02UnboundUnboundUnboundUnboundUnbound
3lcsA02UnboundUnboundUnboundUnboundUnbound
3lctA02UnboundUnboundUnboundUnboundUnbound
4dceA02UnboundUnboundUnboundUnboundUnbound
4dceB02UnboundUnboundUnboundUnboundUnbound
4fnwA02UnboundUnboundUnboundUnboundUnbound
4fnxA02UnboundUnboundUnboundUnboundUnbound
4fnyA02UnboundUnboundUnboundUnboundUnbound
4fnzA02UnboundUnboundUnboundUnboundUnbound
4fobA02UnboundUnboundUnboundUnboundUnbound
4focA02UnboundUnboundUnboundUnboundUnbound
4fodA02UnboundUnboundUnboundUnboundUnbound
2kupBUnboundUnboundUnboundUnboundUnbound
2ys5BUnboundUnboundUnboundUnboundUnbound

Active-site residues
resource
Literature [5] & Swiss-prot;Q9UM73
pdbCatalytic residuesCofactor-binding residuesModified residuescomment
            
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
2xb7A02ASP 1249;ARG 1253
ASN 1254;ASP 1270(Magnesium binding)
                              
invisible 1275-1288
2xbaA02ASP 1249;ARG 1253
ASN 1254;ASP 1270(Magnesium binding)
TYR 1278(auto-phosphorylation)
invisible 1279-1288
2xp2A02ASP 1249;ARG 1253
ASN 1254;ASP 1270(Magnesium binding)
TYR 1278(auto-phosphorylation)
invisible 1281-1289
2yfxA02ASP 1249;ARG 1253
ASN 1254;ASP 1270(Magnesium binding)
TYR 1278(auto-phosphorylation)
invisible 1280-1285
2yhvA02ASP 1249;ARG 1253
ASN 1254;ASP 1270(Magnesium binding)
TYR 1278(auto-phosphorylation)
invisible 1280-1285
2yjrA02ASP 1249;ARG 1253
ASN 1254;ASP 1270(Magnesium binding)
                              
invisible 1274-1287
2yjsA02ASP 1249;ARG 1253
ASN 1254;ASP 1270(Magnesium binding)
TYR 1278(auto-phosphorylation)
invisible 1280-1287
3aoxA02ASP 1249;ARG 1253
ASN 1254;ASP 1270(Magnesium binding)
TYR 1278(auto-phosphorylation)
invisible 1281-1287
3l9pA02ASP 1249;ARG 1253
ASN 1254;ASP 1270(Magnesium binding)
TYR 1278(auto-phosphorylation)
 
3lcsA02ASP 1249;ARG 1253
ASN 1254;ASP 1270(Magnesium binding)
TYR 1278(auto-phosphorylation)
 
3lctA02ASP 1249;ARG 1253
ASN 1254;ASP 1270(Magnesium binding)
TYR 1278(auto-phosphorylation)
 
4dceA02ASP 1249;ARG 1253
ASN 1254;ASP 1270(Magnesium binding)
                              
invisible 1273-1286
4dceB02ASP 1249;ARG 1253
ASN 1254;ASP 1270(Magnesium binding)
                              
invisible 1273-1287
4fnwA02ASP 1249;ARG 1253
ASN 1254;ASP 1270(Magnesium binding)
TYR 1278(auto-phosphorylation)
invisible 1280-1287
4fnxA02ASP 1249;ARG 1253
ASN 1254;ASP 1270(Magnesium binding)
TYR 1278(auto-phosphorylation)
invisible 1279-1287
4fnyA02ASP 1249;ARG 1253
ASN 1254;ASP 1270(Magnesium binding)
                              
invisible 1216-1219, 1272-1287
4fnzA02ASP 1249;ARG 1253
ASN 1254;ASP 1270(Magnesium binding)
                              
invisible 1273-1287
4fobA02ASP 1249;ARG 1253
ASN 1254;ASP 1270(Magnesium binding)
TYR 1278(auto-phosphorylation)
invisible 1216-1218, 1281-1286
4focA02ASP 1249;ARG 1253
ASN 1254;ASP 1270(Magnesium binding)
TYR 1278(auto-phosphorylation)
invisible 1280-1287
4fodA02ASP 1249;ARG 1253
ASN 1254;ASP 1270(Magnesium binding)
TYR 1278(auto-phosphorylation)
invisible 1281-1287
2kupB 
 
 
 
2ys5B 
 
 
 


references
[1]
CommentsINTERACTION WITH PTN, FUNCTION.
PubMed ID11278720
JournalJ Biol Chem
Year2001
Volume276
Pages16772-9
AuthorsStoica GE, Kuo A, Aigner A, Sunitha I, Souttou B, Malerczyk C, Caughey DJ, Wen D, Karavanov A, Riegel AT, Wellstein A
TitleIdentification of anaplastic lymphoma kinase as a receptor for the growth factor pleiotrophin.
[2]
CommentsINTERACTION WITH MDK, FUNCTION.
PubMed ID12122009
JournalJ Biol Chem
Year2002
Volume277
Pages35990-8
AuthorsStoica GE, Kuo A, Powers C, Bowden ET, Sale EB, Riegel AT, Wellstein A
TitleMidkine binds to anaplastic lymphoma kinase (ALK) and acts as a growth factor for different cell types.
[3]
CommentsSUBSTRATE SPECIFICITY.
PubMed ID15938644
JournalBiochemistry
Year2005
Volume44
Pages8533-42
AuthorsTartari CJ, Mologni L, Scapozza L, Gambacorti-Passerini C, Pinna LA
TitleUnique substrate specificity of anaplastic lymphoma kinase (ALK): development of phosphoacceptor peptides for the assay of ALK activity.
[4]
PubMed ID18070884
JournalJ Biol Chem
Year2008
Volume283
Pages3743-50
AuthorsTartari CJ, Gunby RH, Coluccia AM, Sottocornola R, Cimbro B, Scapozza L, Donella-Deana A, Pinna LA, Gambacorti-Passerini C
TitleCharacterization of some molecular mechanisms governing autoactivation of the catalytic domain of the anaplastic lymphoma kinase.
[5]
CommentsX-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 1072-1410.
PubMed ID20632993
JournalBiochem J
Year2010
Volume430
Pages425-37
AuthorsLee 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
TitleCrystal structure of the ALK (anaplastic lymphoma kinase) catalytic domain.
Related PDB3l9p,3lcs,3lct
Related UniProtKBQ9UM73
[6]
CommentsX-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF 1094-1407 IN COMPLEX WITH INHIBITOR.
PubMed ID20695522
JournalBiochemistry
Year2010
Volume49
Pages6813-25
AuthorsBossi 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
TitleCrystal structures of anaplastic lymphoma kinase in complex with ATP competitive inhibitors.
Related PDB2xb7,2xba
Related UniProtKBQ9UM73
[7]
PubMed ID20454865
JournalJ Struct Funct Genomics
Year2010
Volume11
Pages125-41
AuthorsKoshiba 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
TitleStructural 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 PDB2kup,2ys5
[8]
CommentsX-RAY CRYSTALLOGRAPHY (1.75 ANGSTROMS) OF 1069-1411 IN COMPLEX WITH INHIBITOR, ENZYME REGULATION.
PubMed ID21575866
JournalCancer Cell
Year2011
Volume19
Pages679-90
AuthorsSakamoto H, Tsukaguchi T, Hiroshima S, Kodama T, Kobayashi T, Fukami TA, Oikawa N, Tsukuda T, Ishii N, Aoki Y
TitleCH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant.
Related PDB3aox
Related UniProtKBQ9UM73
[9]
PubMed ID21812414
JournalJ Med Chem
Year2011
Volume54
Pages6342-6363
AuthorsCui 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
TitleStructure 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 PDB2xp2
Related UniProtKBQ9UM73
[10]
PubMed ID22263917
JournalJ Med Chem
Year2012
Volume55
Pages1698-705
AuthorsBryan MC, Whittington DA, Doherty EM, Falsey JR, Cheng AC, Emkey R, Brake RL, Lewis RT
TitleRapid development of piperidine carboxamides as potent and selective anaplastic lymphoma kinase inhibitors.
Related PDB4dce
[11]
PubMed ID22734674
JournalJ Med Chem
Year2012
Volume55
Pages6523-40
AuthorsLewis 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
TitleThe 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 PDB4fob,4foc,4fod
[12]
PubMed ID22932897
JournalJ Biol Chem
Year2012
Volume287
Pages37447-57
AuthorsEpstein LF, Chen H, Emkey R, Whittington DA
TitleThe R1275Q neuroblastoma mutant and certain ATP-competitive inhibitors stabilize alternative activation loop conformations of anaplastic lymphoma kinase.
Related PDB4fnw,4fnx,4fny,4fnz

comments
This enzyme belongs to the insulin receptor kinase superfamily (see [5]).
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 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).

createdupdated
2011-11-042013-01-17


Copyright: Nozomi Nagano, JST & CBRC-AIST
Funded by PRESTO/Japan Science and Technology Corporation (JST) (December 2001 - November 2004)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2006)
Funded by Grant-in-Aid for Scientific Research (B)/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (September 2005 - September 2008)
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)
Supported by the commission for the Development of Artificial Gene Synthesis Technology for Creating Innovative Biomaterial from the Ministry of Economy, Trade and Industry (METI) (October 2012 - )
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