User:Alice Harmon/Sandbox 1: Difference between revisions

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[[Image:1ATP.jpg|left|]]

Eukaryotic protein kinases are enzymes that transfer a phosphoryl group (-PO32-) from adenosine triphosphate (or more rarely from adenosine diphosphate) to the hydroxyl group of serine, threonine, or tyrosine residue of a protein substrate. Phosphorylation of the substrate can affect its activity and/or conformation and, in turn, the physiogy of the cell. Protein kinases act as switches that turn on or off metabolic and signaling pathways, and they play central roles in development and responses to the environment. Also, unregulated versions of kinases that arise from tumor-promoting viruses promote cancer in humans. The number of protein kinase genes (and the percentage of the genome) in bakers yeast<ref>PMID: 9020587</ref>, humans<ref> PMID:12471243</ref> and rice <ref>PMID:17172291</ref> are 113 (2%),518 (2%), and 1429 (5%), respectively. The catalytic domains of these enzymes occur alone or with other functional domains in a single polypetide chain. Protein kinases may be monomeric or multimeric or found in complexes with regulatory proteins.

Eukaryotic protein kinases are enzymes that transfer a phosphoryl group (-PO32-) from adenosine triphosphate (or more rarely from adenosine diphosphate) to the hydroxyl group of serine, threonine, or tyrosine residue of a protein substrate. Phosphorylation of the substrate can affect its activity and/or conformation and, in turn, the physiogy of the cell. Protein kinases act as switches that turn on or off metabolic and signaling pathways, and they play central roles in development and responses to the environment. Also, unregulated versions of kinases that arise from tumor-promoting viruses promote cancer in humans. The number of protein kinase genes (and the percentage of the genome) in bakers yeast<ref>PMID: 9020587</ref>, humans<ref> PMID:12471243</ref> and rice<ref>PMID:17172291</ref> are 113 (2%),518 (2%), and 1429 (5%), respectively. The catalytic domains of these enzymes occur alone or with other functional domains in a single polypetide chain. Protein kinases may be monomeric or multimeric or found in complexes with regulatory proteins.

This first section of this article relates the twelve conserved subdomains recognized in the primary structures of protein kinase catalytic domains<ref name='Hanksa'>PMID:3291115</ref><ref name='Hanksb'>PMID: 7768349</ref> to the three-dimensional structure of protein kinase A (also called PKA or [[CAMP-dependent protein kinase]])<ref name = 'Knightona' PMID: 1862342</ref><ref name = 'Knightonb' PMID: 1862343</ref>. The results described in these classic papers apply to the basic structure of the great range of eukaryotic protein kinases known today.

This first section of this article relates the twelve conserved subdomains recognized in the primary structures of protein kinase catalytic domains<ref name='Hanksa'>PMID:3291115</ref><ref name='Hanksb'>PMID: 7768349</ref> to the three-dimensional structure of protein kinase A (also called PKA or [[CAMP-dependent protein kinase]])<ref name = 'Knightona'> PMID:1862342</ref><ref name = 'Knightonb'>PMID: 1862343</ref>. The results described in these classic papers apply to the basic structure of the great range of eukaryotic protein kinases known today.

The second section of this article examines functional structures and assemblies of protein kinase catalytic and compares active and inactive conformations.

The second section of this article examines functional structures and assemblies of protein kinase catalytic domains and compares active and inactive conformations.

==Twelve Conserved Subdomains==

~~Following is~~ a ~~tour of~~ the twelve conserved subdomains (numbered starting at the amino terminal end of the catalytic domain~~) defined by Hanks and Hunter and using 1atp as a model~~.

The following tour uses [[1atp]]<ref name = 'Knightonb'>PMID: 1862343</ref> as a model to showcase the twelve conserved subdomains defined by Hanks and Hunter<ref name='Hanksb'>PMID: 7768349</ref>. The subdomains are numbered starting at the amino terminal end of the catalytic domain.

The crystal structure [[1atp]] contains the mouse PKA catalytic subunit (blue cartoon), inhibitor protein PKI (yellow cartoon), ATP (CPK wireframe), and two manganese ions (green spheres). The model ~~at the left illustrates~~ that catalytic domains of eukaryotic protein kinases have a small lobe and a large lobe (seen at the top and bottom of the model, respectively), and the catalytic cleft is located between them. The small lobe binds ATP and the large lobe binds the protein substrate modeled here by the inhibitor peptide~~, which~~ has an alanine substituted for the serine in the phosphorylation motif RRxS. All of the molecular scenes include ATP, and some include the inhibitor peptide to illustrate kinase/substrate interactions.

The crystal structure [[1atp]] contains the mouse PKA catalytic subunit (blue cartoon), inhibitor protein PKI (yellow cartoon), ATP (CPK wireframe), and two manganese ions (green spheres). The still image of the model shows that catalytic domains of eukaryotic protein kinases have a small lobe and a large lobe (seen at the top and bottom of the model, respectively), and that the catalytic cleft, marked by the bound ATP molecule, is located between them. The small lobe binds ATP and the large lobe binds the protein substrate, modeled here by the inhibitor peptide PKI. PKI has an alanine substituted for the serine in the phosphorylation motif RRxS, and thus is unable to be phosphorylated. All of the molecular scenes in the tour include ATP, and some include the inhibitor peptide to illustrate kinase/substrate interactions.

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===Active and inactive structures===

The kinase structure used in the above tour is that of the active conformation of PKA. Following is a comparison of this active conformation, with its particular arrangement of structural elements, to the inactive conformation. While active conformations of protein kinases are very similar, there is great variation in the inactive conformations of protein kinases, but all involve misalignment of one or more of the structures, subdomain III (C-helix in PKA) and the catalytic, magnesium binding, and activation loops<ref name = "TaylorTIBS"/>.

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 [[Image:1ATP.jpg|left|]]
-Eukaryotic protein kinases are enzymes that transfer a phosphoryl group (-PO<sub>3</sub><sup>2-</sup>) from adenosine triphosphate (or more rarely from adenosine diphosphate) to the hydroxyl group of serine, threonine, or tyrosine residue of a protein substrate. Phosphorylation of the substrate can affect its activity and/or conformation and, in turn, the physiogy of the cell. Protein kinases act as switches that turn on or off metabolic and signaling pathways, and they play central roles in development and responses to the environment. Also, unregulated versions of kinases that arise from tumor-promoting viruses promote cancer in humans.   The number of protein kinase genes (and the percentage of the genome) in bakers yeast<ref>PMID: 9020587</ref>, humans<ref> PMID:12471243</ref> and rice <ref>PMID:17172291</ref> are 113 (2%),518 (2%), and 1429 (5%), respectively. The catalytic domains of these enzymes occur alone or with other functional domains in a single polypetide chain. Protein kinases may be monomeric or multimeric or found in complexes with regulatory proteins.
+Eukaryotic protein kinases are enzymes that transfer a phosphoryl group (-PO<sub>3</sub><sup>2-</sup>) from adenosine triphosphate (or more rarely from adenosine diphosphate) to the hydroxyl group of serine, threonine, or tyrosine residue of a protein substrate. Phosphorylation of the substrate can affect its activity and/or conformation and, in turn, the physiogy of the cell. Protein kinases act as switches that turn on or off metabolic and signaling pathways, and they play central roles in development and responses to the environment. Also, unregulated versions of kinases that arise from tumor-promoting viruses promote cancer in humans.   The number of protein kinase genes (and the percentage of the genome) in bakers yeast<ref>PMID: 9020587</ref>, humans<ref> PMID:12471243</ref> and rice<ref>PMID:17172291</ref> are 113 (2%),518 (2%), and 1429 (5%), respectively. The catalytic domains of these enzymes occur alone or with other functional domains in a single polypetide chain. Protein kinases may be monomeric or multimeric or found in complexes with regulatory proteins.
-This first section of this article relates the twelve conserved subdomains recognized in the primary structures of protein kinase catalytic domains<ref name='Hanksa'>PMID:3291115</ref><ref name='Hanksb'>PMID: 7768349</ref> to the three-dimensional structure of protein kinase A (also called PKA or [[CAMP-dependent protein kinase]])<ref name = 'Knightona' PMID: 1862342</ref><ref name = 'Knightonb' PMID: 1862343</ref>. The results described in these classic papers apply to the basic structure of the great range of eukaryotic protein kinases known today.
+This first section of this article relates the twelve conserved subdomains recognized in the primary structures of protein kinase catalytic domains<ref name='Hanksa'>PMID:3291115</ref><ref name='Hanksb'>PMID: 7768349</ref> to the three-dimensional structure of protein kinase A (also called PKA or [[CAMP-dependent protein kinase]])<ref name = 'Knightona'> PMID:1862342</ref><ref name = 'Knightonb'>PMID: 1862343</ref>. The results described in these classic papers apply to the basic structure of the great range of eukaryotic protein kinases known today.
-The second section of this article examines functional structures and assemblies of protein kinase catalytic and compares active and inactive conformations.
+The second section of this article examines functional structures and assemblies of protein kinase catalytic domains and compares active and inactive conformations.
 ==Twelve Conserved Subdomains==
-Following is a tour of the twelve conserved subdomains (numbered starting at the amino terminal end of the catalytic domain) defined by Hanks and Hunter and using 1atp as a model.
+The following tour uses [[1atp]]<ref name = 'Knightonb'>PMID: 1862343</ref> as a model to showcase the twelve conserved subdomains defined by Hanks and Hunter<ref name='Hanksb'>PMID: 7768349</ref>. The subdomains are numbered starting at the amino terminal end of the catalytic domain.
-The crystal structure [[1atp]] contains the mouse PKA catalytic subunit (blue cartoon), inhibitor protein PKI (yellow cartoon), ATP (CPK wireframe), and two manganese ions (green spheres). The model at the left illustrates that catalytic domains of eukaryotic protein kinases have a small lobe and a large lobe (seen at the top and bottom of the model, respectively), and the catalytic cleft is located between them. The small lobe binds ATP and the large lobe binds the protein substrate modeled here by the inhibitor peptide, which has an alanine substituted for the serine in the phosphorylation motif RRxS. All of the molecular scenes include ATP, and some include the inhibitor peptide to illustrate kinase/substrate interactions.
+The crystal structure [[1atp]] contains the mouse PKA catalytic subunit (blue cartoon), inhibitor protein PKI (yellow cartoon), ATP (CPK wireframe), and two manganese ions (green spheres). The still image of the model shows that catalytic domains of eukaryotic protein kinases have a small lobe and a large lobe (seen at the top and bottom of the model, respectively), and that the catalytic cleft, marked by the bound ATP molecule, is located between them. The small lobe binds ATP and the large lobe binds the protein substrate, modeled here by the inhibitor peptide PKI. PKI has an alanine substituted for the serine in the phosphorylation motif RRxS, and thus is unable to be phosphorylated.  All of the molecular scenes in the tour include ATP, and some include the inhibitor peptide to illustrate kinase/substrate interactions.
 <Structure load='1ATP' size='500' frame='true' align='right' caption='1atp - Protein kinase A catalytic subunit in complex with ATP (wireframe), manganese, and inhibitor peptide PKI' scene='55/555705/Pkaall/1' />
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 ===Active and inactive structures===
+The kinase structure used in the above tour is that of the active conformation of PKA. Following is a comparison of this active conformation, with its particular arrangement of structural elements, to the inactive conformation. While active conformations of protein kinases are very similar, there is great variation in the inactive conformations of protein kinases, but all involve misalignment of one or more of the structures, subdomain III (C-helix in PKA) and the catalytic, magnesium binding, and activation loops<ref name = "TaylorTIBS"/>.