User:Alice Harmon/Sandbox 1: Difference between revisions

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This article describes the general structure of protein kinase domains. It is based on the analysis of the primary structure of protein kinases by Hanks, Quinn, and Hunter <ref> PMID: 3291115</ref> in which the amino acid sequences of 65 protein kinases were aligned, and the revised analysis by Hanks and Hunter <ref> PMID: 7768349</ref>, and on the first three-dimensional structure of protein kinase to be published, that of protein kinase A (also called PKA or [[CAMP-dependent protein kinase]]) by Knighton et al.<ref> PMID: 1862342</ref>. The results described in these papers apply to the basic structure of the great range of eukaryotic protein kinases known today.

The crystal structure [[1atp]] contains the 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 site is located in a cleft between them. The small lobe binds ATP and the large lobe binds the protein substrate. the inhibitor peptide has an alanine substituted for the serine in the phosphorylation motif RRxS. All of the molecular scenes below 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 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 site is located in a cleft between them. The small lobe binds ATP and the large lobe binds the protein substrate. the inhibitor peptide has an alanine substituted for the serine in the phosphorylation motif RRxS. All of the molecular scenes below include ATP, and some include the inhibitor peptide to illustrate kinase/substrate interactions.

=Twelve Conserved Subdomains=

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<scene name='55/555705/Subdomainvii/1'>Subdomain VII</scene> contains two beta strands link by the Mg-binding loop with the DFG motif. The <scene name='55/555705/Dfg/2'>Aspartate in this motif (blue ball and stick)</scene> chelates a Mg<sup>2+</sup> ion (Mn<sup>2+</sup> in the 1atp crystal structure) that bridges the gamma and beta phosphates of ATP and positions the gamma phosphate for transfer to the substrate.

<scene name='55/555705/Subdomainviii/1'>Subdomain VIII</scene> contains several important features. The APE motif is located at the carboxyl end of this subdomain and the <scene name='55/555705/Ape/1'>glutamate </scene>(blue ball and stick) in this motif forms a salt bridge with an arginine (yellow ball and stick) in in Subdomain XI. This salt bridge is critical for forming the stable kinase core and it provides an anchor for the movement of the activation loop (see below). In many protein kinases there is a phosphorylatable residue seven to ten residues upstream of the APE motif. In PKA it is a <scene name='55/555705/Phosphothreonine/1'>phosphothreonine</scene> (blue ball and stick with the phosphate in CPK), which forms an ionic bond with the arginine (yellow ball and stick) in the YRDLKPEN motif of the catalytic loop and helps to position it for catalysis. Kinases that don't have a phosphorylatable residue in this loop often have an acididc residue that can form the salt bridge. Between the phosphorylated residue and the APE motif lies the <scene name='55/555705/Pplus1/1'>P+1 loop</scene> which interacts with the residue adjacent to the phosphorylated residue of the peptide substrate.

<scene name='55/555705/Subdomainviii/1'>Subdomain VIII</scene> contains several important features. The APE motif is located at the carboxyl end of this subdomain and the <scene name='55/555705/Ape/1'>glutamate </scene>(blue ball and stick) in this motif forms a salt bridge with an arginine (yellow ball and stick) in in Subdomain XI. This salt bridge is critical for forming the stable kinase core and it provides an anchor for the movement of the activation loop (see below). In many protein kinases there is a phosphorylatable residue seven to ten residues upstream of the APE motif. In PKA it is a <scene name='55/555705/Phosphothreonine/1'>phosphothreonine</scene> (blue ball and stick with the phosphate in CPK), which forms an ionic bond with the arginine (yellow ball and stick) in the YRDLKPEN motif of the catalytic loop and helps to position it for catalysis. Kinases that don't have a phosphorylatable residue in this loop often have an acididc residue that can form the salt bridge. Between the phosphorylated residue and the APE motif lies the <scene name='55/555705/Pplus1/1'>P+1 loop</scene> (ball and stick), which interacts with the residue adjacent to the phosphorylated residue of the peptide substrate. The "P" residue is the one that is phosphoryated in the substrate, and the "P + 1" residue is the next residue in the sequence.

<scene name='55/555705/Subdomainix/1'>Subdomain IX</scene> is a very hydrophobic alpha helix (helix F in ~~bovine~~ PKA). It contains ~~and~~ invariant aspartate residue that is discussed below.

<scene name='55/555705/Subdomainix/1'>Subdomain IX</scene> is a very hydrophobic alpha helix (helix F in mamallian PKA). It contains an invariant aspartate residue that is discussed below.

<scene name='55/555705/Subdomainx/1'>Subdomain X</scene> and <scene name='55/555705/Subdomainxi/1'>Subdomain XI</scene> contain three alpha helices (G, H, and I in ~~bovine~~ PKA) that form the kinase core and which are involved in binding substrate proteins.

<scene name='55/555705/Subdomainx/1'>Subdomain X</scene> and <scene name='55/555705/Subdomainxi/1'>Subdomain XI</scene> contain three alpha helices (G, H, and I in mamallian PKA) that form the kinase core and which are involved in binding substrate proteins.

=Beyond the Conserved Subdomains=

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 This article describes the general structure of protein kinase domains. It is based on the analysis of the primary structure of protein kinases by Hanks, Quinn, and Hunter <ref> PMID: 3291115</ref> in which the amino acid sequences of 65 protein kinases were aligned, and the revised analysis by Hanks and Hunter <ref> PMID: 7768349</ref>, and on the first three-dimensional structure of protein kinase to be published, that of protein kinase A (also called PKA or [[CAMP-dependent protein kinase]]) by Knighton et al.<ref> PMID: 1862342</ref>. The results described in these papers apply to the basic structure of the great range of eukaryotic protein kinases known today.
-The crystal structure [[1atp]] contains the 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 site is located in a cleft between them. The small lobe binds ATP and the large lobe binds the protein substrate. the inhibitor peptide has an alanine substituted for the serine in the phosphorylation motif RRxS. All of the molecular scenes below 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 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 site is located in a cleft between them. The small lobe binds ATP and the large lobe binds the protein substrate. the inhibitor peptide has an alanine substituted for the serine in the phosphorylation motif RRxS. All of the molecular scenes below include ATP, and some include the inhibitor peptide to illustrate kinase/substrate interactions.
 =Twelve Conserved Subdomains=
@@ Line 34: / Line 34: @@
 <scene name='55/555705/Subdomainvii/1'>Subdomain VII</scene> contains two beta strands link by the Mg-binding loop with the DFG motif. The <scene name='55/555705/Dfg/2'>Aspartate in this motif (blue ball and stick)</scene> chelates a Mg<sup>2+</sup> ion (Mn<sup>2+</sup> in the 1atp crystal structure) that bridges the gamma and beta phosphates of ATP and positions the gamma phosphate for transfer to the substrate.
-<scene name='55/555705/Subdomainviii/1'>Subdomain VIII</scene> contains several important features. The APE motif is located at the carboxyl end of this subdomain and the <scene name='55/555705/Ape/1'>glutamate  </scene>(blue ball and stick) in this motif forms a salt bridge with an arginine (yellow ball and stick) in in Subdomain XI. This salt bridge is critical for forming the stable kinase core and it provides an anchor for the movement of the activation loop (see below). In many protein kinases there is a phosphorylatable residue seven to ten residues upstream of the APE motif. In PKA it is a <scene name='55/555705/Phosphothreonine/1'>phosphothreonine</scene> (blue ball and stick with the phosphate in CPK), which forms an ionic bond with the arginine (yellow ball and stick) in the YRDLKPEN motif of the catalytic loop and helps to position it for catalysis.  Kinases that don't have a phosphorylatable residue in this loop often have an acididc residue that can form the salt bridge. Between the phosphorylated residue and the APE motif lies the <scene name='55/555705/Pplus1/1'>P+1 loop</scene> which interacts with the residue adjacent to the phosphorylated residue of the peptide substrate.
+<scene name='55/555705/Subdomainviii/1'>Subdomain VIII</scene> contains several important features. The APE motif is located at the carboxyl end of this subdomain and the <scene name='55/555705/Ape/1'>glutamate  </scene>(blue ball and stick) in this motif forms a salt bridge with an arginine (yellow ball and stick) in in Subdomain XI. This salt bridge is critical for forming the stable kinase core and it provides an anchor for the movement of the activation loop (see below). In many protein kinases there is a phosphorylatable residue seven to ten residues upstream of the APE motif. In PKA it is a <scene name='55/555705/Phosphothreonine/1'>phosphothreonine</scene> (blue ball and stick with the phosphate in CPK), which forms an ionic bond with the arginine (yellow ball and stick) in the YRDLKPEN motif of the catalytic loop and helps to position it for catalysis.  Kinases that don't have a phosphorylatable residue in this loop often have an acididc residue that can form the salt bridge. Between the phosphorylated residue and the APE motif lies the <scene name='55/555705/Pplus1/1'>P+1 loop</scene> (ball and stick), which interacts with the residue adjacent to the phosphorylated residue of the peptide substrate. The "P" residue is the one that is phosphoryated in the substrate, and the "P + 1" residue is the next residue in the sequence.
-<scene name='55/555705/Subdomainix/1'>Subdomain IX</scene> is a very hydrophobic alpha helix (helix F in bovine PKA). It contains and invariant aspartate residue that is discussed below.
+<scene name='55/555705/Subdomainix/1'>Subdomain IX</scene> is a very hydrophobic alpha helix (helix F in mamallian PKA). It contains an invariant aspartate residue that is discussed below.
-<scene name='55/555705/Subdomainx/1'>Subdomain X</scene> and <scene name='55/555705/Subdomainxi/1'>Subdomain XI</scene> contain three alpha helices (G, H, and I in bovine PKA) that form the kinase core and which are involved in binding substrate proteins.
+<scene name='55/555705/Subdomainx/1'>Subdomain X</scene> and <scene name='55/555705/Subdomainxi/1'>Subdomain XI</scene> contain three alpha helices (G, H, and I in mamallian PKA) that form the kinase core and which are involved in binding substrate proteins.
 =Beyond the Conserved Subdomains=