Sandbox Reserved 708: Difference between revisions
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<!-- PLEASE ADD YOUR CONTENT BELOW HERE --> | <!-- PLEASE ADD YOUR CONTENT BELOW HERE --> | ||
[[Image:1j1c01.gif |thumb||left| 1j1c 3D structure | [[Image:1j1c01.gif |thumb||left| 1j1c 3D structure ]] | ||
== Description == | == Description == | ||
[[Image:1j1cplot.gif |thumb||400 px||right| [http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=1j1c&template=protein.html&r=wiring&l=1&chain=A Sequence of 1j1c]]] | |||
The Glycogen Synthase Kinase 3 beta- GSK-3β, also known as the tau-protein-kinase I, is a serine protein kinase that participates in many different pathways regulating critical cellular functions as the structure, the gene expression, the mobility, and the apoptosis,<ref name="SINR"> "Structural insight into nucleotide recognition in tau-protein kinase I/glycogen synthase kinase 3 beta." | The Glycogen Synthase Kinase 3 beta- GSK-3β, also known as the tau-protein-kinase I, is a serine protein kinase that participates in many different pathways regulating critical cellular functions as the structure, the gene expression, the mobility, and the apoptosis,<ref name="SINR"> "Structural insight into nucleotide recognition in tau-protein kinase I/glycogen synthase kinase 3 beta." | ||
Aoki, M., Yokota, T., Sugiura, I., Sasaki, C., Hasegawa, T., Okumura, C., Ishiguro, K., Kohno, T., Sugio, S., Matsuzaki, T. | Aoki, M., Yokota, T., Sugiura, I., Sasaki, C., Hasegawa, T., Okumura, C., Ishiguro, K., Kohno, T., Sugio, S., Matsuzaki, T. | ||
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Considering the roles plaid by GSK3 in promoting both pathological features of Alzheimer disease, GSK3-inhibitors may act positively in the therapy of Alzheimer’s patients. But due to the importance of its role in numerous cellular functions, it is important to develop inhibitors that do not affect or suppress its primary activity,<ref> "GSK3 inhibitors show benefits in an Alzheimer's disease (AD) model of neurodegeneration but adverse effects in control animals.". 5 Hu S (Feb 2009).Neurobiol Dis. 33 (2): 193-206. doi:10.1016/j.nbd.2008.10.007. PMID 19038340.</ref>. | Considering the roles plaid by GSK3 in promoting both pathological features of Alzheimer disease, GSK3-inhibitors may act positively in the therapy of Alzheimer’s patients. But due to the importance of its role in numerous cellular functions, it is important to develop inhibitors that do not affect or suppress its primary activity,<ref> "GSK3 inhibitors show benefits in an Alzheimer's disease (AD) model of neurodegeneration but adverse effects in control animals.". 5 Hu S (Feb 2009).Neurobiol Dis. 33 (2): 193-206. doi:10.1016/j.nbd.2008.10.007. PMID 19038340.</ref>. | ||
There are two isoforms of GSK-3: GSK3α and GSK3β,<ref name="GSK3 IDT" />. Our concern focuses on GSK3β.The two main mechanisms that affect the activity of the kinase are its inhibition by phosphorylation of serine-9 and its activity enhancement by phosphorylation of tyrosine-216,<ref name="GSK3β DPA"/> | There are two isoforms of GSK-3: GSK3α and GSK3β,<ref name="GSK3 IDT" />. Our concern focuses on GSK3β.The two main mechanisms that affect the activity of the kinase are its inhibition by phosphorylation of serine-9 and its activity enhancement by phosphorylation of tyrosine-216,<ref name="GSK3β DPA"/>. | ||
GSK-3β can phosphorylate tau on Ser-199, Thr-231, Ser-396, Ser-400, Ser-404, and Ser-413 in vivo and in vitro,<ref> "Structure and Pathology of Tau Protein in Alzheimer Disease." | GSK-3β can phosphorylate tau on Ser-199, Thr-231, Ser-396, Ser-400, Ser-404, and Ser-413 in vivo and in vitro,<ref> "Structure and Pathology of Tau Protein in Alzheimer Disease." | ||
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This protein is composed by two subunits A (green) and B (blue) linked by 12 hydrogen bonds in order to stabilize the molecule. But only four are shown (with red dashed lines) | This protein is composed by two subunits A (green) and B (blue) linked by 12 hydrogen bonds in order to stabilize the molecule. But only four are shown on the 3D picture (with red dashed lines) with their <scene name='Sandbox_Reserved_708/Hbonds_amino_acids/7'>amino acids (17)</scene> engaged: Ser-66, Ser-215,Tyr-216, Arg-220, Gly-230, Asp-260, Gly-262, Val-263, Tyr-288, Ser-715,Tyr-716, Arg-720, Asp-760,Val-763, Asp-764, Tyr-788 and Glu-790. The full list of interactions between these amino-acids is shown in this [http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=1j1c&template=interfaces.html&o=RESIDUE&l=1 page]. | ||
This structure also possesses <scene name='Sandbox_Reserved_708/Mg_ions/3'>two divalent cations Mg2+</scene> as well as <scene name='Sandbox_Reserved_708/Adp/3'>two molecules of ADP</scene>(Adenosine DiPhosphate). Arg-141 is one of the key residues for <scene name='Sandbox_Reserved_708/Adp_recognition_by_arg141/1'>specific ATP/ADP recognition</scene> by GSK3,<ref name="SINR"/>. | This structure also possesses <scene name='Sandbox_Reserved_708/Mg_ions/3'>two divalent cations Mg2+</scene> as well as <scene name='Sandbox_Reserved_708/Adp/3'>two molecules of ADP</scene>(Adenosine DiPhosphate). Arg-141 is one of the key residues for <scene name='Sandbox_Reserved_708/Adp_recognition_by_arg141/1'>specific ATP/ADP recognition</scene> by GSK3,<ref name="SINR"/>. You can find more details about this recognition in the following two links, [http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=1j1c&template=ligands.html&l=1.1 for the ADP], [http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=1j1c&template=ligands.html&o=METAL&l=1.1 for Mg2+]. | ||
The <scene name='Sandbox_Reserved_708/Catalytic_site/7'>amino acids</scene> engaged in the catalytic site of the protein are Asp-181, Lys-183, Gln-185, Asn-186 and Ser-219. They are polar and localised in 3' end. | The <scene name='Sandbox_Reserved_708/Catalytic_site/7'>amino acids</scene> engaged in the catalytic site of the protein are Asp-181, Lys-183, Gln-185, Asn-186 and Ser-219. They are polar and localised in 3' end. | ||