Schultz et al. (1998) Proc. Natl. Acad. Sci. USA 95, 5857-5864
Letunic et al. (2012) Nucleic Acids Res , doi:10.1093/nar/gkr931

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S_TK_X Extension to Ser/Thr-type protein kinases

SMART accession number:	SM00133
Description:
Interpro abstract (IPR000961):	Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity [(PUBMED:3291115)]: Serine/threonine-protein kinases Tyrosine-protein kinases Dual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins) Protein kinase function is evolutionarily conserved from Escherichia coli to human [(PUBMED:12471243)]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation [(PUBMED:12368087)]. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [(PUBMED:15078142)], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [(PUBMED:15320712)]. The AGC (cAMP-dependent, cGMP-dependent and protein kinase C) protein kinase family embraces a collection of protein kinases that display a high degree of sequence similarity within their respective kinase domains. AGC kinase proteins are characterised by three conserved phosphorylation sites that critically regulate their function. The first one is located in an activation loop in the centre of the kinase domain. The two other phosphorylation sites are located outside the kinase domain in a conserved region on its C-terminal side, the AGC-kinase C-terminal domain. These sites serves as phosphorylation-regulated switches to control both intra- and inter-molecular interactions. Without these priming phosphorylations, the kinases are catalytically inactive [(PUBMED:12495431), (PUBMED:11709088), (PUBMED:15209375)]. Several structures of the AGC-kinase C-terminal domain have been solved. The first phosphorylation site is located in a turn motif, the second one at the end of the domain in an hydrophobic pocket. In PKB the phosphorylated hydrophobic motif engages a hydrophobic groove within the N-lobe of the kinase domain which orders alpha helices close to the active site [(PUBMED:12434148)].
GO process:	protein phosphorylation (GO:0006468)
GO function:	protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524)
Family alignment:	View or CHROMA formatCLUSTALW formatMSF formatFASTA formatPIR format

There are 3834 S_TK_X domains in 3829 proteins in SMART's nrdb database.

Click on the following links for more information.

• Evolution (species in which this domain is found)

• Click on to expand nodes. To display all proteins with a S_TK_X domain in a specific node, click on it.

  This tree shows only several representative species. The complete taxonomic breakdown of all proteins with S_TK_X domain is also avaliable.

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  Go to specific node: Anopheles gambiae, Arabidopsis thaliana, Caenorhabditis elegans, Drosophila melanogaster, Homo sapiens, Mus musculus, Rattus norvegicus, Saccharomyces cerevisiae, Takifugu rubripes

• Disease (disease genes where sequence variants are found in this domain)

• SwissProt sequences and OMIM curated human diseases associated with missense mutations within the S_TK_X domain.

  Protein	Disease
  Protein kinase C gamma type (P05129) (SMART)	OMIM:176980: PROTEIN KINASE C, GAMMA; PRKCG
  Rhodopsin kinase (Q15835) (SMART)	OMIM:180381: Oguchi disease-2 OMIM:258100:

• Metabolism (metabolic pathways involving proteins which contain this domain)

• Click the image to view the interactive version of the map in iPath

  % proteins involved KEGG pathway ID Description 6.60 map04010 MAPK signaling pathway 4.74 map04720 Long-term potentiation 4.74 map04910 Insulin signaling pathway 4.64 map04530 Tight junction 4.49 map04914 Progesterone-mediated oocyte maturation 4.20 map04310 Wnt signaling pathway 4.20 map04540 Gap junction 3.42 map04510 Focal adhesion 3.42 map04012 ErbB signaling pathway 3.37 map04020 Calcium signaling pathway 3.37 map04916 Melanogenesis 3.37 map04150 mTOR signaling pathway 3.13 map04210 Apoptosis 2.78 map04740 Olfactory transduction 2.59 map04370 VEGF signaling pathway 2.59 map05214 Glioma 2.59 map05223 Non-small cell lung cancer 2.25 map04670 Leukocyte transendothelial migration 2.25 map04730 Long-term depression 2.00 map05221 Acute myeloid leukemia 1.95 map04742 Taste transduction 1.95 map04912 GnRH signaling pathway 1.95 map04340 Hedgehog signaling pathway 1.66 map04350 TGF-beta signaling pathway 1.42 map04070 Phosphatidylinositol signaling system 1.42 map04650 Natural killer cell mediated cytotoxicity 1.17 map05222 Small cell lung cancer 1.17 map05213 Endometrial cancer 1.17 map04662 B cell receptor signaling pathway 1.17 map05212 Pancreatic cancer 1.17 map04630 Jak-STAT signaling pathway 1.17 map05220 Chronic myeloid leukemia 1.17 map04920 Adipocytokine signaling pathway 1.17 map04664 Fc epsilon RI signaling pathway 1.17 map05210 Colorectal cancer 1.17 map04620 Toll-like receptor signaling pathway 1.17 map05215 Prostate cancer 1.17 map04660 T cell receptor signaling pathway 1.17 map05211 Renal cell carcinoma 1.17 map05218 Melanoma 0.83 map04810 Regulation of actin cytoskeleton 0.83 map04360 Axon guidance 0.29 map00632 Benzoate degradation via CoA ligation 0.29 map00562 Inositol phosphate metabolism 0.24 map04111 Cell cycle - yeast This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with S_TK_X domain which could be assigned to a KEGG orthologous group, and not all proteins containing S_TK_X domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.

• Structure (3D structures containing this domain)

• 3D Structures of S_TK_X domains in PDB

  PDB code	Main view	Title
  1apm		2.0 angstrom refined crystal structure of the catalytic subunit of camp-dependent protein kinase complexed with a peptide inhibitor and detergent
  1atp		2.2 angstrom refined crystal structure of the catalytic subunit of camp-dependent protein kinase complexed with mnatp and a peptide inhibitor
  1bkx		A binary complex of the catalytic subunit of camp-dependent protein kinase and adenosine further defines conformational flexibility
  1bx6		Crystal structure of the potent natural product inhibitor balanol in complex with the catalytic subunit of camp- dependent protein kinase
  1cdk		Camp-dependent protein kinase catalytic subunit (e.c.2.7.1.37) (protein kinase a) complexed with protein kinase inhibitor peptide fragment 5-24 (pki(5-24) isoelectric variant ca) and mn2+ adenylyl imidodiphosphate (mnamp-pnp) at ph 5.6 and 7c and 4c
  1cmk		Crystal structures of the myristylated catalytic subunit of camp-dependent protein kinase reveal open and closed conformations
  1ctp		Structure of the mammalian catalytic subunit of camp- dependent protein kinase and an inhibitor peptide displays an open conformation
  1fmo		Crystal structure of a polyhistidine-tagged recombinant catalytic subunit of camp-dependent protein kinase complexed with the peptide inhibitor pki(5-24) and adenosine
  1fot		Structure of the unliganded camp-dependent protein kinase catalytic subunit from saccharomyces cerevisiae
  1gzk		Molecular mechanism for the regulation of protein kinase b/ akt by hydrophobic motif phosphorylation
  1gzn		Structure of pkb kinase domain
  1gzo		Structure of protein kinase b unphosphorylated
  1j3h		Crystal structure of apoenzyme camp-dependent protein kinase catalytic subunit
  1jbp		Crystal structure of the catalytic subunit of camp- dependent protein kinase complexed with a substrate peptide, adp and detergent
  1jlu		Crystal structure of the catalytic subunit of camp- dependent protein kinase complexed with a phosphorylated substrate peptide and detergent
  1l3r		Crystal structure of a transition state mimic of the catalytic subunit of camp-dependent protein kinase
  1mrv		Crystal structure of an inactive akt2 kinase domain
  1mry		Crystal structure of an inactive akt2 kinase domain
  1o6k		Structure of activated form of pkb kinase domain s474d with gsk3 peptide and amp-pnp
  1o6l		Crystal structure of an activated akt/protein kinase b (pkb-pif chimera) ternary complex with amp-pnp and gsk3 peptide
  1omw		Crystal structure of the complex between g protein-coupled receptor kinase 2 and heterotrimeric g protein beta 1 and gamma 2 subunits
  1q24		Pka double mutant model of pkb in complex with mgatp
  1q61		Pka triple mutant model of pkb
  1q62		Pka double mutant model of pkb
  1q8t		The catalytic subunit of camp-dependent protein kinase (pka) in complex with rho-kinase inhibitor y-27632
  1q8u		The catalytic subunit of camp-dependent protein kinase in complex with rho-kinase inhibitor h-1152p
  1q8w		The catalytic subunit of camp-dependent protein kinase in complex with rho-kinase inhibitor fasudil (ha-1077)
  1rdq		Hydrolysis of atp in the crystal of y204a mutant of camp- dependent protein kinase
  1re8		Crystal structure of camp-dependent protein kinase complexed with balanol analog 2
  1rej		Crystal structure of camp-dependent protein kinase complexed with balanol analog 1
  1rek		Crystal structure of camp-dependent protein kinase complexed with balanol analog 8
  1smh		Protein kinase a variant complex with completely ordered n- terminal helix
  1stc		Camp-dependent protein kinase, alpha-catalytic subunit in complex with staurosporine
  1sve		Crystal structure of protein kinase a in complex with azepane derivative 1
  1svg		Crystal structure of protein kinase a in complex with azepane derivative 4
  1svh		Crystal structure of protein kinase a in complex with azepane derivative 8
  1syk		Crystal structure of e230q mutant of camp-dependent protein kinase reveals unexpected apoenzyme conformation
  1szm		Dual binding mode of bisindolylmaleimide 2 to protein kinase a (pka)
  1veb		Crystal structure of protein kinase a in complex with azepane derivative 5
  1xh4		Crystal structures of protein kinase b selective inhibitors in complex with protein kinase a and mutants
  1xh5		Crystal structures of protein kinase b selective inhibitors in complex with protein kinase a and mutants
  1xh6		Crystal structures of protein kinase b selective inhibitors in complex with protein kinase a and mutants
  1xh7		Crystal structures of protein kinase b selective inhibitors in complex with protein kinase a and mutants
  1xh8		Crystal structures of protein kinase b selective inhibitors in complex with protein kinase a and mutants
  1xh9		Crystal structures of protein kinase b selective inhibitors in complex with protein kinase a and mutants
  1xha		Crystal structures of protein kinase b selective inhibitors in complex with protein kinase a and mutants
  1xjd		Crystal structure of pkc-theta complexed with staurosporine at 2a resolution
  1ydr		Structure of camp-dependent protein kinase, alpha-catalytic subunit in complex with h7 protein kinase inhibitor 1-(5- isoquinolinesulfonyl)-2-methylpiperazine
  1yds		Structure of camp-dependent protein kinase, alpha-catalytic subunit in complex with h8 protein kinase inhibitor [n-(2- methylamino)ethyl]-5-isoquinolinesulfonamide
  1ydt		Structure of camp-dependent protein kinase, alpha-catalytic subunit in complex with h89 protein kinase inhibitor n-[2- (4-bromocinnamylamino)ethyl]-5-isoquinoline
  1ym7		G protein-coupled receptor kinase 2 (grk2)
  1zrz		Crystal structure of the catalytic domain of atypical protein kinase c-iota
  2acx		Crystal structure of g protein coupled receptor kinase 6 bound to amppnp
  2bcj		Crystal structure of g protein-coupled receptor kinase 2 in complex with galpha-q and gbetagamma subunits
  2c1a		Structure of camp-dependent protein kinase complexed with isoquinoline-5-sulfonic acid (2-(2-(4-chlorobenzyloxy) ethylamino)ethyl)amide
  2c1b		Structure of camp-dependent protein kinase complexed with ( 4r,2s)-5'-(4-(4-chlorobenzyloxy)pyrrolidin-2- ylmethanesulfonyl)isoquinoline
  2cpk		Crystal structure of the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase
  2erz		Crystal structure of c-amp dependent kinase (pka) bound to hydroxyfasudil
  2esm		Crystal structure of rock 1 bound to fasudil
  2etk		Crystal structure of rock 1 bound to hydroxyfasudil
  2etr		Crystal structure of rock i bound to y-27632
  2f2u		Crystal structure of the rho-kinase kinase domain
  2f7e		Pka complexed with (s)-2-(1h-indol-3-yl)-1-(5-isoquinolin-6- yl-pyridin-3-yloxymethyl-etylamine
  2f7x		Protein kinase a bound to (s)-2-(1h-indol-3-yl)-1-[5-((e)-2- pyridin-4-yl-vinyl)-pyridin-3-yloxymethyl]-ethylamine
  2f7z		Protein kinase a bound to (r)-1-(1h-indol-3-ylmethyl)-2-(2- pyridin-4-yl-[1,7]naphtyridin-5-yloxy)-ehylamine
  2gfc		Camp-dependent protein kinase pka catalytic subunit with pki-5-24
  2gnf		Protein kinase a fivefold mutant model of rho-kinase with y-
  2gng		Protein kinase a fivefold mutant model of rho-kinase
  2gnh		Pka five fold mutant model of rho-kinase with h1152p
  2gni		Pka fivefold mutant model of rho-kinase with inhibitor fasudil (ha1077)
  2gnj		Pka three fold mutant model of rho-kinase with y-27632
  2gnl		Pka threefold mutant model of rho-kinase with inhibitor h- 1152p
  2gu8		Discovery of 2-pyrimidyl-5-amidothiophenes as novel and potent inhibitors for akt: synthesis and sar studies
  2h9v		Structural basis for induced-fit binding of rho-kinase to the inhibitor y27632
  2i0e		Structure of catalytic domain of human protein kinase c beta ii complexed with a bisindolylmaleimide inhibitor
  2jdo		Structure of pkb-beta (akt2) complexed with isoquinoline-5- sulfonic acid (2-(2-(4-chlorobenzyloxy) ethylamino)ethyl) amide
  2jdr		Structure of pkb-beta (akt2) complexed with the inhibitor a-
  2jds		Structure of camp-dependent protein kinase complexed with a-
  2jdt		Structure of pka-pkb chimera complexed with isoquinoline-5- sulfonic acid (2-(2-(4-chlorobenzyloxy) ethylamino)ethyl) amide
  2jdv		Structure of pka-pkb chimera complexed with a-443654
  2jed		The crystal structure of the kinase domain of the protein kinase c theta in complex with nvp-xaa228 at 2.32a resolution.
  2oh0		Crystal structure of protein kinase a in complex with pyridine-pyrazolopyridine based inhibitors
  2ojf		Crystal structure of protein kinase a in complex with pyridine-pyrazolopyridine based inhibitors
  2qcs		A complex structure between the catalytic and regulatory subunit of protein kinase a that represents the inhibited state
  2qur		Crystal structure of f327a/k285p mutant of camp-dependent protein kinase
  2qvs		Crystal structure of type iia holoenzyme of camp-dependent protein kinase
  2r5t		Crystal structure of inactive serum and glucocorticoid- regulated kinase 1 in complex with amp-pnp
  2uvx		Structure of pka-pkb chimera complexed with 7-azaindole
  2uvy		Structure of pka-pkb chimera complexed with methyl-(4-(9h- purin-6-yl)-benzyl)-amine
  2uvz		Structure of pka-pkb chimera complexed with c-phenyl-c-(4-( 9h-purin-6-yl)-phenyl)-methylamine
  2uw0		Structure of pka-pkb chimera complexed with 6-(4-(4-(4- chloro-phenyl)-piperidin-4-yl)-phenyl)-9h-purine
  2uw3		Structure of pka-pkb chimera complexed with 5-methyl-4- phenyl-1h-pyrazole
  2uw4		Structure of pka-pkb chimera complexed with 2-(4-(5-methyl- 1h-pyrazol-4-yl)-phenyl)-ethylamine
  2uw5		Structure of pka-pkb chimera complexed with (r)-2-(4- chloro-phenyl)-2-(4-1h-pyrazol-4-yl)-phenyl)-ethylamine
  2uw6		Structure of pka-pkb chimera complexed with (s)-2-(4- chloro-phenyl)-2-(4-1h-pyrazol-4-yl)-phenyl)-ethylamine
  2uw7		Structure of pka-pkb chimera complexed with 4-(4-chloro- phenyl)-4-(4-(1h-pyrazol-4-yl)-phenyl)-piperidine
  2uw8		Structure of pka-pkb chimera complexed with 2-(4-chloro- phenyl)-2-phenyl-ethylamine
  2uw9		Structure of pkb-beta (akt2) complexed with 4-(4-chloro- phenyl)-4-(4-(1h-pyrazol-4-yl)-phenyl)-piperidine
  2uzt		Pka structures of akt, indazole-pyridine inhibitors
  2uzu		Pka structures of indazole-pyridine series of akt inhibitors
  2uzv		Pka structures of indazole-pyridine series of akt inhibitors
  2uzw		Pka structures of indazole-pyridine series of akt inhibitors
  2v55		Mechanism of multi-site phosphorylation from a rock-i:rhoe complex structure
  2vd5		Structure of human myotonic dystrophy protein kinase in complex with the bisindoylmaleide inhibitor bim viii
  2vnw		Structure of pka-pkb chimera complexed with (1-(9h-purin-6- yl)piperidin-4-yl)methanamine
  2vny		Structure of pka-pkb chimera complexed with (1-(9h-purin-6- yl)piperidin-4-yl)amine
  2vo0		Structure of pka-pkb chimera complexed with c-(4-(4- chlorophenyl)-1-(7h-pyrrolo(2,3-d)pyrimidin-4-yl)piperidin- 4-yl)methylamine
  2vo3		Structure of pka-pkb chimera complexed with c-(4-(4- chlorophenyl)-1-(7h-pyrrolo(2,3-d)pyrimidin-4-yl)piperidin- 4-yl)methylamine
  2vo6		Structure of pka-pkb chimera complexed with 4-(4- chlorobenzyl)-1-(7h-pyrrolo(2,3-d)pyrimidin-4-yl)piperidin- 4-ylamine
  2vo7		Structure of pka complexed with 4-(4-chlorobenzyl)-1-(7h- pyrrolo(2,3-d)pyrimidin-4-yl)piperidin-4-ylamine
  2z7q		Crystal structure of the n-terminal kinase domain of human rsk-1 bound to amp-pcp
  2z7r		Crystal structure of the n-terminal kinase domain of human rsk1 bound to staurosporine
  2z7s		Crystal structure of the n-terminal kinase domain of human rsk1 bound to purvalnol a
  3a60		Crystal structure of unphosphorylated p70s6k1 (form i)
  3a61		Crystal structure of unphosphorylated p70s6k1 (form ii)
  3a62		Crystal structure of phosphorylated p70s6k1
  3bwj		Complex of pka with the bisubstrate protein kinase inhibitor lead compound arc-1034
  3c4w		Crystal structure of g protein coupled receptor kinase 1 bound to atp and magnesium chloride at 2.7a
  3c4x		Crystal structure of g protein coupled receptor kinase 1 bound to atp and magnesium chloride at 2.9a
  3c4y		Crystal structure of apo form of g protein coupled receptor kinase 1 at 7.51a
  3c4z		Crystal structure of g protein coupled receptor kinase 1 bound to adp and magnesium chloride at 1.84a
  3c50		Crystal structure of g protein coupled receptor kinase 1 bound to adp and magnesium chloride at 2.6a
  3c51		Crystal structure of g protein coupled receptor kinase 1 bound to adp and magnesium chloride at 3.55a
  3cik		Human grk2 in complex with gbetagamma subunits
  3cqu		Crystal structure of akt-1 complexed with substrate peptide and inhibitor
  3cqw		Crystal structure of akt-1 complexed with substrate peptide and inhibitor
  3d0e		Crystal structure of human akt2 in complex with gsk690693
  3d9v		Crystal structure of rock i bound to h-1152p a di- methylated variant of fasudil
  3dnd		Camp-dependent protein kinase pka catalytic subunit with pki-5-24
  3dne		Camp-dependent protein kinase pka catalytic subunit with pki-5-24
  3e87		Crystal structures of the kinase domain of akt2 in complex with atp-competitive inhibitors
  3e88		Crystal structures of the kinase domain of akt2 in complex with atp-competitive inhibitors
  3e8c		Crystal structures of the kinase domain of pka in complex with atp-competitive inhibitors
  3e8d		Crystal structures of the kinase domain of akt2 in complex with atp-competitive inhibitors
  3e8e		Crystal structures of the kinase domain of pka in complex with atp-competitive inhibitors
  3fhi		Crystal structure of a complex between the catalytic and regulatory (ri{alpha}) subunits of pka
  3fjq		Crystal structure of camp-dependent protein kinase catalytic subunit alpha in complex with peptide inhibitor pki alpha (6-25)
  3hdm		Crystal structure of serum and glucocorticoid-regulated kinase 1 in complex with compound 1
  3hdn		Crystal structure of serum and glucocorticoid-regulated kinase 1 in complex with compound 2
  3idb		Crystal structure of (108-268)riib:c holoenzyme of camp- dependent protein kinase
  3idc		Crystal structure of (102-265)riib:c holoenzyme of camp- dependent protein kinase
  3iw4		Crystal structure of pkc alpha in complex with nvp-aeb071

• Links (links to other resources describing this domain)

• INTERPRO	IPR000961

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