Literature summary for 2.7.12.1 extracted from

Alexeeva, M.; Aberg, E.; Engh, R.A.; Rothweiler, U.
The structure of a dual-specificity tyrosine phosphorylation-regulated kinase 1A-PKC412 complex reveals disulfide-bridge formation with the anomalous catalytic loop HRD(HCD) cysteine (2015), Acta Crystallogr. Sect. D, 71, 1207-1215.

Application

Application	Comment	Organism
diagnostics	DYRK1A is a risk factor for Alzheimer's disease, enabling detection of the disease prior to the development of behavioural symptoms by analyzing human plasma	Homo sapiens

Cloned(Commentary)

Cloned (Comment)	Organism
recombinant expression of His6-tagged Dyrk1b kinase domain, residues 78-451	Homo sapiens
the dyrk1a gene is located in the Down syndrome critical region (DSCR) on chromosome 21 and full or partial trisomy of DSCR in Down syndrome (DS) leads to overexpression of DYRK1A, recombinant expression of His6-tagged Dyrk1a kinase domain, residues 126-490	Homo sapiens

Crystallization (Commentary)

Crystallization (Comment)	Organism
purified enzyme DYRK1A bound to inhibitor midostaurin, sitting drop vapour diffusion method, mixing of 200 nl of 7-10 mg/ml protein in 50 mM MOPS, pH 6.8, 50 mM KCl, 2 mM 2-mercaptoethanol, with 200 nl of precipitant solution containing 10-16% PEG 3350, 0.1 M potassium thiocyanate, 0.1 M KCl (or 0.1 M NaCl or 0.1 M LiCl), for co-crystallization with the inhibitor midostaurin, protein is mixed in a 1:1 ratio with the inhibitor in crystallization solution, containing 100 mM potassium thiocyanate, 50-100 mM LiCl (or NaCl or KCl), and 10-16% PEG 3350, to give a final drop size of 0.004 ml, by hanging drop vapour diffusion method, 5-7 days at room temperature, X-ray diffraction structure determination and analysis at 2.6 A resolution	Homo sapiens
purified enzyme DYRK1B bound to inhibitor midostaurin, X-ray diffraction structure determination and analysis	Homo sapiens

Crystallization (Comment)

Organism

purified enzyme DYRK1A bound to inhibitor midostaurin, sitting drop vapour diffusion method, mixing of 200 nl of 7-10 mg/ml protein in 50 mM MOPS, pH 6.8, 50 mM KCl, 2 mM 2-mercaptoethanol, with 200 nl of precipitant solution containing 10-16% PEG 3350, 0.1 M potassium thiocyanate, 0.1 M KCl (or 0.1 M NaCl or 0.1 M LiCl), for co-crystallization with the inhibitor midostaurin, protein is mixed in a 1:1 ratio with the inhibitor in crystallization solution, containing 100 mM potassium thiocyanate, 50-100 mM LiCl (or NaCl or KCl), and 10-16% PEG 3350, to give a final drop size of 0.004 ml, by hanging drop vapour diffusion method, 5-7 days at room temperature, X-ray diffraction structure determination and analysis at 2.6 A resolution

Homo sapiens

purified enzyme DYRK1B bound to inhibitor midostaurin, X-ray diffraction structure determination and analysis

Homo sapiens

Inhibitors

Inhibitors	Comment	Organism	Structure
harmine	-	Homo sapiens
midostaurin	i.e. PKC412, a derivative of the broad-spectrum kinase inhibitor staurosporine, an alkaloid isolated from Streptomyces staurosoreus; i.e. PKC412, a derivative of the broad-spectrum kinase inhibitor staurosporine, an alkaloid isolated from Streptomyces staurosoreus. Enzyme binding structure analysis, overview	Homo sapiens

KM Value [mM]

KM Value [mM]	KM Value Maximum [mM]	Substrate	Comment	Organism
additional information	-	additional information	Michaelis-Menten kinetics	Homo sapiens
0.0807	-	ATP	pH 6.8, 22°C	Homo sapiens
0.1185	-	ATP	pH 6.8, 22°C	Homo sapiens

Metals/Ions

Metals/Ions	Comment	Organism	Structure
Mg2+	required	Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.	Reac.
ATP + a protein	Homo sapiens	-	ADP + a phosphoprotein	-	?

Organism

Organism	UniProt	Comment	Textmining
Homo sapiens	Q13627	-	-
Homo sapiens	Q9Y463	-	-

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
ATP + a protein	-	Homo sapiens	ADP + a phosphoprotein	-	?
ATP + RRRFRPASPLRGPPK	i.e. DYRKtide	Homo sapiens	ADP + RRRFRPApSPLRGPPK	-	?

Synonyms

Synonyms	Comment	Organism
dual-specificity tyrosine phosphorylation-regulated kinase 1A	-	Homo sapiens
dual-specificity tyrosine phosphorylation-regulated kinase 1B	-	Homo sapiens
DYRK1A	-	Homo sapiens
DYRK1B	-	Homo sapiens

Temperature Optimum [°C]

Temperature Optimum [°C]	Temperature Optimum Maximum [°C]	Comment	Organism
22	-	assay at room temperature	Homo sapiens

Temperature Stability [°C]

Temperature Stability Minimum [°C]	Temperature Stability Maximum [°C]	Comment	Organism
additional information	-	inhibitors PKC412 and harmine elevate the melting point in buffer of the enzyme from 51°C to 53°C and 57°C, respectively	Homo sapiens

pH Optimum

pH Optimum Minimum	pH Optimum Maximum	Comment	Organism
6.8	-	assay at	Homo sapiens

Cofactor

Cofactor	Comment	Organism	Structure
ATP	-	Homo sapiens

Ki Value [mM]

Ki Value [mM]	Ki Value maximum [mM]	Inhibitor	Comment	Organism	Structure
0.0000254	-	midostaurin	pH 6.8, 22°C	Homo sapiens
0.0000284	-	midostaurin	pH 6.8, 22°C	Homo sapiens

IC50 Value

IC50 Value	IC50 Value Maximum	Comment	Organism	Inhibitor	Structure
0.000059	-	pH 6.8, 22°C	Homo sapiens	midostaurin
0.000066	-	pH 6.8, 22°C	Homo sapiens	midostaurin

General Information

General Information	Comment	Organism
malfunction	the dyrk1a gene is located in the Down syndrome critical region (DSCR) on chromosome 21 and full or partial trisomy of DSCR in Down syndrome (DS) leads to overexpression of DYRK1A	Homo sapiens
physiological function	dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a protein kinase associated with neuronal development and brain physiology. Activity of DYRK1A to prime the tau protein for further phosphorylation by GSK-3beta. This leads to the hyperphosphorylation of tau, followed by selfaggregation into neurofibrillary tangles, which are the primary biomarker of Alzheimer's disease	Homo sapiens