Reviewed, UniProtKB/Swiss-Prot P03176 (KITH_HHV11)

Names and origin

Protein names

Recommended name:
    Thymidine kinase
    EC=2.7.1.21

Gene names

Name:	TK
Synonyms:	UL23

Organism

Human herpesvirus 1 (strain 17) (HHV-1) (Human herpes simplex virus 1) [Complete proteome]

Taxonomic identifier

10299 [NCBI]

Taxonomic lineage

Viruses › dsDNA viruses, no RNA stage › Herpesvirales › Herpesviridae › Alphaherpesvirinae › Simplexvirus

Virus host

Homo sapiens (Human) [TaxID: 9606]

Protein attributes

Sequence length	376 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	In latent infection, may allow the virus to be reactivated and to grow in cells lacking a high concentration of phosphorylated nucleic acid precursors, such as nerve cells that do not replicate their genome By similarity.
Catalytic activity	ATP + thymidine = ADP + thymidine 5'-phosphate.
Subunit structure	Homodimer.
Biotechnological use	Used in molecular biology as a selectable marker to identify transfected eukaryotic cells. Used in cancer suicide gene therapy to selectively kill transformed cells.
Miscellaneous	Phosphorylates and thereby activates certain drugs like acyclovir (ACV), valaciclovir, and famciclovir to a toxic form, that leads to successful suppression of the infection, while the uninfected cell does not have this ability because it lacks TK. Mutations in thymidine kinase may induce HSV resistance to antiviral therapies in immunocompromised patients. The most frequently observed resistant strains are unable to express TK and are avirulent in animal models of disease. Resistance may be acquired less frequently by selecting variants which no longer recognize ACV or ACV triphosphate as substrates but which retain normal functions.
Sequence similarities	Belongs to the herpesviruses thymidine kinase family.

Ontologies

Keywords
Biological process	DNA synthesis
Developmental stage	Early protein
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Transferase
Technical term	3D-structure Complete proteome
Gene Ontology (GO)
Biological process	DNA replication Inferred from electronic annotation. Source: UniProtKB-KW TMP biosynthetic process Inferred from electronic annotation. Source: InterPro
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW thymidine kinase 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 – 376

376

Thymidine kinase

PRO_0000175069

Regions

Nucleotide binding

56 – 63

8

ATP

Region

168 – 176

9

Nucleoside-binding

Natural variations

Natural variant

6

1

C → G

Natural variant

23

1

N → S

Natural variant

36

1

E → K

Natural variant

42

1

P → L

Natural variant

251

1

C → G

Experimental info

Mutagenesis

162

1

D → N: Inactivates enzyme.

Sequence conflict

265

1

T → A in CAA32315. Ref.1

Sequence conflict

321

1

S → P in CAA32315. Ref.1

Secondary structure

1

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376

Helix Strand Turn

Details...

Beta strand

48 – 54

7

Helix

62 – 68

7

Beta strand

77 – 81

5

Helix

85 – 89

5

Beta strand

92 – 94

3

Helix

96 – 108

13

Helix

114 – 139

26

Helix

140 – 142

3

Beta strand

143 – 148

6

Beta strand

156 – 162

7

Helix

165 – 169

5

Helix

171 – 178

8

Helix

184 – 192

9

Beta strand

202 – 207

6

Helix

210 – 218

9

Helix

229 – 250

22

Helix

255 – 258

4

Helix

259 – 262

4

Helix

284 – 286

3

Helix

288 – 292

5

Helix

295 – 297

3

Helix

306 – 320

15

Beta strand

323 – 328

6

Helix

333 – 343

11

Helix

344 – 346

3

Beta strand

349 – 354

6

Helix

357 – 372

16

Sequences

	Sequence		Length	Mass (Da)
	P03176-1 [UniParc]. Last modified July 15, 1998. Version 4. Checksum: 7E58BB575143B328	FASTA	376	40,972
	10 20 30 40 50 60 MASYPCHQHA SAFDQAARSR GHNNRRTALR PRRQQEATEV RPEQKMPTLL RVYIDGPHGM 70 80 90 100 110 120 GKTTTTQLLV ALGSRDDIVY VPEPMTYWRV LGASETIANI YTTQHRLDQG EISAGDAAVV 130 140 150 160 170 180 MTSAQITMGM PYAVTDAVLA PHIGGEAGSS HAPPPALTLI FDRHPIAALL CYPAARYLMG 190 200 210 220 230 240 SMTPQAVLAF VALIPPTLPG TNIVLGALPE DRHIDRLAKR QRPGERLDLA MLAAIRRVYG 250 260 270 280 290 300 LLANTVRYLQ CGGSWREDWG QLSGTAVPPQ GAEPQSNAGP RPHIGDTLFT LFRAPELLAP 310 320 330 340 350 360 NGDLYNVFAW ALDVLAKRLR SMHVFILDYD QSPAGCRDAL LQLTSGMVQT HVTTPGSIPT 370 ICDLARTFAR EMGEAN

References

[1]	"The complete DNA sequence of the long unique region in the genome of herpes simplex virus type 1." McGeoch D.J., Dalrymple M.A., Davison A.J., Dolan A., Frame M.C., McNab D., Perry L.J., Scott J.E., Taylor P. J. Gen. Virol. 69:1531-1574(1988) [PubMed: 2839594] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[2]	"The nucleotide sequence and transcript map of the herpes simplex virus thymidine kinase gene." McKnight S.L. Nucleic Acids Res. 8:5949-5964(1980) [PubMed: 6258156] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"The three-dimensional structure of thymidine kinase from herpes simplex virus type 1." Wild K., Bohner T., Aubry A., Folkers G., Schulz G.E. FEBS Lett. 368:289-292(1995) [PubMed: 7628623] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS) OF 34-376.
[4]	"Crystal structures of the thymidine kinase from herpes simplex virus type-1 in complex with deoxythymidine and ganciclovir." Brown D.G., Visse R., Sandhu G., Davies A., Rizkallah P.J., Melitz C., Summers W.C., Sanderson M.R. Nat. Struct. Biol. 2:876-881(1995) [PubMed: 7552712] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS).
[5]	"The structures of thymidine kinase from herpes simplex virus type 1 in complex with substrates and a substrate analogue." Wild K., Bohner T., Folkers G., Schulz G.E. Protein Sci. 6:2097-2106(1997) [PubMed: 9336833] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.75 ANGSTROMS) OF 34-376.
[6]	"Exploring the active site of herpes simplex virus type-1 thymidine kinase by X-ray crystallography of complexes with aciclovir and other ligands." Champness J.N., Bennett M.S., Wien F., Visse R., Summers W.C., Herdewijn P., de Clerq E., Ostrowski T., Jarvest R.L., Sanderson M.R. Proteins 32:350-361(1998) [PubMed: 9715911] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS).
[7]	"Structure to 1.9-A resolution of a complex with herpes simplex virus type-1 thymidine kinase of a novel, non-substrate inhibitor: X-ray crystallographic comparison with binding of aciclovir." Bennett M.S., Wien F., Champness J.N., Batuwangala T., Rutherford T., Summers W.C., Sun H., Wright G., Sanderson M.R. FEBS Lett. 443:121-125(1999) [PubMed: 9989588] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS).
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBLGenBankDDBJ

X14112 Genomic DNA. Translation: CAA32315.1.
V00470 Genomic DNA. Translation: CAA23742.1.

PIR

KIBE17. E30084.

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1E2H	X-ray	1.90	A/B	46-376	[»]
1E2I	X-ray	1.90	A/B	46-376	[»]
1E2J	X-ray	2.50	A/B	46-376	[»]
1E2K	X-ray	1.70	A/B	46-376	[»]
1E2L	X-ray	2.40	A/B	46-376	[»]
1E2M	X-ray	2.20	A/B	46-376	[»]
1E2N	X-ray	2.20	A/B	46-376	[»]
1E2P	X-ray	2.50	A/B	46-376	[»]
1KI2	X-ray	2.20	A/B	46-376	[»]
1KI3	X-ray	2.37	A/B	46-376	[»]
1KI4	X-ray	2.34	A/B	46-376	[»]
1KI6	X-ray	2.37	A	46-376	[»]
			B	46-376	[»]
1KI7	X-ray	2.20	A/B	46-376	[»]
1KI8	X-ray	2.20	A/B	46-376	[»]
1KIM	X-ray	2.14	A/B	11-376	[»]
1OF1	X-ray	1.95	A/B	1-376	[»]
1P7C	X-ray	2.10	A/B	34-376	[»]
1QHI	X-ray	1.90	A/B	11-376	[»]
1VTK	X-ray	2.75	A	34-376	[»]
2KI5	X-ray	1.90	A/B	11-376	[»]
2VTK	X-ray	2.80	A	34-376	[»]
3VTK	X-ray	3.00	A	34-376	[»]

DisProt

DP00419.

ModBase

Search...

Enzyme and pathway databases

BRENDA

2.7.1.21. 74785.

Family and domain databases

InterPro

IPR001889. Herpes_TK.
[Graphical view]

Pfam

PF00693. Herpes_TK. 1 hit.
[Graphical view]

ProDom

PD001519. Herpes_TK. 1 hit.
[Graphical view] [Entries sharing at least one domain]

ProtoNet

Search...

Other Resources

BindingDB

P03176.

DrugBank

DB00787. Aciclovir.
DB01004. Ganciclovir.

Entry information

Entry name

KITH_HHV11

Accession

Primary (citable) accession number: P03176

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 21, 1986
Last sequence update:	July 15, 1998
Last modified:	June 16, 2009
This is version 72 of the entry and version 4 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

Virus (Virus annotation project)