P16455 (MGMT_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Methylated-DNA--protein-cysteine methyltransferase
EC=2.1.1.63

Alternative name(s):
6-O-methylguanine-DNA methyltransferase
Short name=MGMT
O-6-methylguanine-DNA-alkyltransferase

Gene names

Name:

MGMT

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	207 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Involved in the cellular defense against the biological effects of O6-methylguanine (O6-MeG) in DNA. Repairs alkylated guanine in DNA by stoichiometrically transferring the alkyl group at the O-6 position to a cysteine residue in the enzyme. This is a suicide reaction: the enzyme is irreversibly inactivated.
Catalytic activity	DNA (containing 6-O-methylguanine) + protein L-cysteine = DNA (without 6-O-methylguanine) + protein S-methyl-L-cysteine.
Cofactor	Binds 1 zinc ion.
Subcellular location	Nucleus.
Miscellaneous	This enzyme catalyzes only one turnover and therefore is not strictly catalytic. According to one definition, an enzyme is a biocatalyst that acts repeatedly and over many reaction cycles.
Sequence similarities	Belongs to the MGMT family.

Ontologies

Keywords
Biological process	DNA damage DNA repair
Cellular component	Nucleus
Coding sequence diversity	Polymorphism
Ligand	DNA-binding Metal-binding Zinc
Molecular function	Methyltransferase Transferase
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	DNA dealkylation involved in DNA repair Inferred from electronic annotation. Source: Compara DNA ligation Traceable author statement Ref.2. Source: ProtInc DNA repair Traceable author statement. Source: Reactome cellular response to ionizing radiation Inferred from electronic annotation. Source: Compara cellular response to organic cyclic compound Inferred from electronic annotation. Source: Compara cellular response to oxidative stress Inferred from electronic annotation. Source: Compara mammary gland epithelial cell differentiation Inferred from electronic annotation. Source: Compara negative regulation of cell death Inferred from electronic annotation. Source: Compara positive regulation of DNA repair Inferred from electronic annotation. Source: Compara regulation of cysteine-type endopeptidase activity involved in apoptotic process Inferred from electronic annotation. Source: Compara response to drug Inferred from electronic annotation. Source: Compara response to ethanol Inferred from electronic annotation. Source: Compara response to folic acid Inferred from electronic annotation. Source: Compara response to toxin Inferred from electronic annotation. Source: Compara
Cellular_component	nucleoplasm Traceable author statement. Source: Reactome
Molecular_function	DNA binding Traceable author statement Ref.2. Source: ProtInc DNA-methyltransferase activity Traceable author statement Ref.1. Source: ProtInc calcium ion binding Inferred from electronic annotation. Source: Compara methylated-DNA-[protein]-cysteine S-methyltransferase activity Inferred from electronic annotation. Source: EC
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 207

207

Methylated-DNA--protein-cysteine methyltransferase

PRO_0000139359

Sites

Active site

145

1

Nucleophile; methyl group acceptor

Metal binding

5

1

Zinc

Metal binding

24

1

Zinc

Metal binding

29

1

Zinc

Metal binding

85

1

Zinc

Binding site

95

1

DNA; via amide nitrogen

Binding site

114

1

DNA

Binding site

115

1

DNA; via amide nitrogen

Binding site

123

1

DNA

Binding site

128

1

DNA

Binding site

151

1

DNA; via amide nitrogen

Natural variations

Natural variant

30

1

E → K.
Corresponds to variant rs2020893 [ dbSNP | Ensembl ].

VAR_014750

Natural variant

53

1

L → F.
Corresponds to variant rs12917 [ dbSNP | Ensembl ].

VAR_056129

Natural variant

58

1

P → S.
Corresponds to variant rs2308322 [ dbSNP | Ensembl ].

VAR_029112

Natural variant

65

1

W → C.
Corresponds to variant rs2282164 [ dbSNP | Ensembl ].

VAR_020354

Natural variant

84

1

L → F.
Corresponds to variant rs12917 [ dbSNP | Ensembl ].

VAR_014751

Natural variant

112

1

I → V.
Corresponds to variant rs2308321 [ dbSNP | Ensembl ].

VAR_056130

Natural variant

143

1

I → V.
Corresponds to variant rs2308321 [ dbSNP | Ensembl ].

VAR_014752

Natural variant

160

1

G → R.
Corresponds to variant rs2308318 [ dbSNP | Ensembl ].

VAR_014753

Natural variant

166

1

E → D.
Corresponds to variant rs2308320 [ dbSNP | Ensembl ].

VAR_014754

Natural variant

178

1

K → R.
Corresponds to variant rs2308327 [ dbSNP | Ensembl ].

VAR_014755

Experimental info

Mutagenesis

114

1

Y → A: Decreases activity towards methylated DNA over 1000-fold. Slightly reduced reactivity with O6-benzylguanine. Ref.12

Mutagenesis

114

1

Y → E: Loss of DNA repair activity. Slightly reduced reactivity with O6-benzylguanine. Ref.12

Mutagenesis

128

1

R → A or D: Decreases activity towards methylated DNA over 1000-fold. No effect on reactivity with O6-benzylguanine. Ref.12 Ref.14

Mutagenesis

128

1

R → G: Loss of DNA repair activity. Ref.12 Ref.14

Mutagenesis

128

1

R → K or L: Slightly reduced DNA repair activity. Ref.12 Ref.14

Mutagenesis

138

1

P → K: Decreased reactivity with O6-benzylguanine. Ref.11

Mutagenesis

140

1

P → A: Decreased reactivity with O6-benzylguanine. Ref.11

Mutagenesis

145

1

C → A: Loss of DNA repair activity. Ref.12 Ref.14

Mutagenesis

156

1

G → A: Decreased reactivity with O6-benzylguanine. Ref.11

Mutagenesis

158

1

Y → A: Reduced DNA repair activity. Decreased reactivity with O6-benzylguanine. Ref.13

Mutagenesis

158

1

Y → F: Slightly reduced DNA repair activity. Ref.13

Sequence conflict

127

1

A → T in AAA52317. Ref.2

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

207

Helix Strand Turn

Details...

Beta strand

8 – 12

5

Beta strand

19 – 24

6

Beta strand

27 – 33

7

Beta strand

50 – 52

3

Helix

57 – 71

15

Helix

73 – 78

6

Helix

87 – 90

4

Helix

94 – 105

12

Helix

114 – 120

7

Turn

124 – 126

3

Helix

127 – 134

8

Beta strand

138 – 140

3

Helix

145 – 147

3

Helix

162 – 171

10

Sequences

	Sequence		Length	Mass (Da)
	P16455 [UniParc]. Last modified August 1, 1990. Version 1. Checksum: 76BBF19DFC4512D6	FASTA	207	21,646
	10 20 30 40 50 60 MDKDCEMKRT TLDSPLGKLE LSGCEQGLHE IKLLGKGTSA ADAVEVPAPA AVLGGPEPLM 70 80 90 100 110 120 QCTAWLNAYF HQPEAIEEFP VPALHHPVFQ QESFTRQVLW KLLKVVKFGE VISYQQLAAL 130 140 150 160 170 180 AGNPKAARAV GGAMRGNPVP ILIPCHRVVC SSGAVGNYSG GLAVKEWLLA HEGHRLGKPG 190 200 LGGSSGLAGA WLKGAGATSG SPPAGRN

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Isolation and structural characterization of a cDNA clone encoding the human DNA repair protein for O6-alkylguanine." Tano K., Shiota S., Collier J., Foote R.S., Mitra S. Proc. Natl. Acad. Sci. U.S.A. 87:686-690(1990) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 1-8.
[2]	"cDNA cloning and chromosomal assignment of the human O6-methylguanine-DNA methyltransferase. cDNA expression in Escherichia coli and gene expression in human cells." Rydberg B., Spurr N., Karran P. J. Biol. Chem. 265:9563-9569(1990) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	"Purification, structure, and biochemical properties of human O6-methylguanine-DNA methyltransferase." Koike G., Maki H., Takeya H., Hayakawa H., Sekiguchi M. J. Biol. Chem. 265:14754-14762(1990) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[4]	"Expression and cloning of complementary DNA for a human enzyme that repairs O6-methylguanine in DNA." Hayakawa H., Koike G., Sekiguchi M. J. Mol. Biol. 213:739-747(1990) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[5]	"Cloning of human full-length CDSs in BD Creator(TM) system donor vector." Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A. Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[6]	"The DNA sequence and comparative analysis of human chromosome 10." Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L., Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K., Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L., Taylor A., Battles J. , Bird C.P., Ainscough R., Almeida J.P., Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J. Nature 429:375-381(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[8]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Placenta.
[9]	"Structural and immunological comparison of indigenous human O6-methylguanine-DNA methyltransferase with that encoded by a cloned cDNA." von Wronski M.A., Shiota S., Tano K., Mitra S., Bigner D.D., Brent T.P. J. Biol. Chem. 266:1064-1070(1991) [PubMed] [Europe PMC] [Abstract] Cited for: PARTIAL PROTEIN SEQUENCE, ALKYL GROUP ACCEPTOR.
[10]	"Specificities of human, rat and E. coli O6-methylguanine-DNA methyltransferases towards the repair of O6-methyl and O6-ethylguanine in DNA." Liem L.-K., Lim A., Li B.F.L. Nucleic Acids Res. 22:1613-1619(1994) [PubMed] [Europe PMC] [Abstract] Cited for: CHARACTERIZATION.
[11]	"Mutations in human O6-alkylguanine-DNA alkyltransferase imparting resistance to O6-benzylguanine." Crone T.M., Goodtzova K., Edara S., Pegg A.E. Cancer Res. 54:6221-6227(1994) [PubMed] [Europe PMC] [Abstract] Cited for: MUTAGENESIS OF PRO-138; PRO-140 AND GLY-156.
[12]	"Alteration of arginine-128 to alanine abolishes the ability of human O6-alkylguanine-DNA alkyltransferase to repair methylated DNA but has no effect on its reaction with O6-benzylguanine." Kanugula S., Goodtzova K., Edara S., Pegg A.E. Biochemistry 34:7113-7119(1995) [PubMed] [Europe PMC] [Abstract] Cited for: MUTAGENESIS OF TYR-114; ARG-128 AND CYS-145.
[13]	"The role of tyrosine-158 in O6-alkylguanine-DNA alkyltransferase activity." Edara S., Goodtzova K., Pegg A.E. Carcinogenesis 16:1637-1642(1995) [PubMed] [Europe PMC] [Abstract] Cited for: MUTAGENESIS OF TYR-158.
[14]	"Active and alkylated human AGT structures: a novel zinc site, inhibitor and extrahelical base binding." Daniels D.S., Mol C.D., Arvai A.S., Kanugula S., Pegg A.E., Tainer J.A. EMBO J. 19:1719-1730(2000) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) IN COMPLEX WITH DNA AND ZINC IONS, MUTAGENESIS OF ARG-128 AND CYS-145.
[15]	"Crystal structure of the human O(6)-alkylguanine-DNA alkyltransferase." Wibley J.E., Pegg A.E., Moody P.C. Nucleic Acids Res. 28:393-401(2000) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 1-176.
[16]	"The structure of the human AGT protein bound to DNA and its implications for damage detection." Duguid E.M., Rice P.A., He C. J. Mol. Biol. 350:657-666(2005) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS) OF 1-179 IN COMPLEX WITH DNA AND ZINC IONS.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

X54228 mRNA. Translation: CAA38137.1.
M29971 mRNA. Translation: AAA59596.1.
M31767 mRNA. Translation: AAA52317.1.
M60761 mRNA. Translation: AAA59594.1.
BT006714 mRNA. Translation: AAP35360.1.
AL157832, AL355531 Genomic DNA. Translation: CAH70060.1.
AL355531, AL157832 Genomic DNA. Translation: CAH72190.1.
CH471066 Genomic DNA. Translation: EAW49166.1.
BC000824 mRNA. Translation: AAH00824.1.

IPI

IPI00028618.

PIR

XUHUMC. A34889.

UniGene

Hs.501522.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1EH6	X-ray	2.00	A	1-207	[»]
1EH7	X-ray	2.00	A	1-207	[»]
1EH8	X-ray	2.50	A	1-207	[»]
1QNT	X-ray	1.90	A	1-176	[»]
1T38	X-ray	3.20	A	1-176	[»]
1T39	X-ray	3.30	A/B	1-176	[»]
1YFH	X-ray	3.01	A/B/C	1-179	[»]

ProteinModelPortal

P16455.

ModBase

Search...

Protein-protein interaction databases

IntAct

P16455. 1 interaction.

STRING

9606.ENSP00000302111.

PTM databases

PhosphoSite

P16455.

Polymorphism databases

DMDM

127069.

Proteomic databases

PaxDb

P16455.

PeptideAtlas

P16455.

PRIDE

P16455.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000306010; ENSP00000302111; ENSG00000170430.

Organism-specific databases

GeneCards

GC10P131195.

H-InvDB

HIX0009309.

HGNC

HGNC:7059. MGMT.

HPA

CAB002786.

MIM

156569. gene.

neXtProt

NX_P16455.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0350.

HOGENOM

HOG000244137.

HOVERGEN

HBG001146.

InParanoid

P16455.

OrthoDB

EOG4SJ5G1.

PhylomeDB

P16455.

Enzyme and pathway databases

BRENDA

2.1.1.63. 2681.

Reactome

REACT_216. DNA Repair.

Gene expression databases

ArrayExpress

P16455.

Bgee

P16455.

CleanEx

HS_MGMT.

Genevestigator

P16455.

GermOnline

ENSG00000170430. Homo sapiens.

Family and domain databases

Gene3D

1.10.10.10. 1 hit.

InterPro

IPR001497. MethylDNA_cys_MeTrfase_AS.
IPR014048. MethylDNA_cys_MeTrfase_DNA-bd.
IPR008332. MethylG_MeTrfase.
IPR011991. WHTH_DNA-bd_dom.
[Graphical view]

Pfam

PF01035. DNA_binding_1. 1 hit.
PF02870. Methyltransf_1N. 1 hit.
[Graphical view]

SUPFAM

SSF46767. MethylDNA_cys_mtrans_DNA_bd. 1 hit.

TIGRFAMs

TIGR00589. ogt. 1 hit.

PROSITE

PS00374. MGMT. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P16455.

ChEMBL

CHEMBL2864.

DrugBank

DB00151. L-Cysteine.

EvolutionaryTrace

P16455.

SOURCE

Search...

Entry information

Entry name

MGMT_HUMAN

Accession

Primary (citable) accession number: P16455
Secondary accession number(s): Q5VY78

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 1, 1990
Last sequence update:	August 1, 1990
Last modified:	May 1, 2013
This is version 143 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.