Sandbox 210: Difference between revisions

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==Structure==
==Structure==


Like most eukaryotic protein kinases, Cdk5 has a catalytic domain flanked with additional domains that are involved in its regulation. The catalytic domain has an N-terminal lobe of beta-sheet and alpha-helical C-domain (C lobe) with an ATP binding site between the two. The alpha-helical structure is called PSAALRE based on the polypeptide sequence. A stretch of 20 residues located centrally at the interphase of N and C lobe can acquire a conformation competent for phosphate transfer and is called the activation loop.<ref name="un" />
The 33 kDa- protein CDK5 consists of an eukaryotic catalytic domain (ePK) that is flanked by other domains involved in the regulation of ePK. CDK5 consists of a C-terminal domain that shows alpha-helical structure (C-lobe) and an N-terminal domain (N-lobe) consisting predominantly of a beta-sheet but also containing an alpha-helix, named alpha C-helix or PSAALRE, based on its amino acid sequence. Between N- and C-lobe the ATP-binding site is located in a deep cleft. Structural changes of the ePK domain are leading to different activation states of the kinase. Only a unique active conformation is able to transfer phosphate from an ATP-molecule onto a substrate. The activation loop or T-loop, a flexible stretch of approximately 20 amino acids between the interface of the C- and N-lobes, is the key for the control of these conformational changes. It provides the association of CDK5 with its activator proteins and is involved in the positioning of ATP. The activator protein of CDK5, p25, presents a cyclin-box fold domain, which is the structural motif found in the cyclins. More precisely, CDK5 binds p25 through its single cyclin box fold (CBF) around the CDK5's PSAALRE helix and the activation loop. The subunit of the CDK5 shares also a very similar three-dimensional (3D) structure with CDK2.<ref name="premier">doi:10.1007/s00894-009-0629-4</ref>
The subunit of the CDK5 shares also a very similar three-dimensional (3D) structure with CDK2.<ref name="premier">doi:10.1007/s00894-009-0629-4</ref>
 
The activator protein of CDK5, p25, presents a cyclin-box fold domain, which is the structural motif found in the cyclins.
Analyses of the crystal structures of CDK5/p25 show the existence of extensive electrostatic and Van Der Waals interactions between the β sheet, and a small loop following the C helix (f-loop) of CDK5, and an helix of p25.
Analyses of the crystal structures of CDK5/p25 show the existence of extensive electrostatic and Van Der Waals interactions between the β sheet, and a small loop following the C helix (f-loop) of CDK5, and an helix of p25.
During the unbinding processes between CDK5 and p25, obvious conformational changes in the C helix and the T loop are observed. The C helix, together with the loop preceding the helix (the p-loop) apparently displaces from its original location towards the p25 side. The distances between the C-alpha carbon atoms of the tip amino acid of the p-loop (Gly43) and the starting amino acid of the C helix (Ser46) before and after pulling are 14.15 Å and 7.23 Å, respectively.<ref name="premier">doi:10.1007/s00894-009-0629-4</ref>
During the unbinding processes between CDK5 and p25, obvious conformational changes in the C helix and the T loop are observed. The C helix, together with the loop preceding the helix (the p-loop) apparently displaces from its original location towards the p25 side. The distances between the C-alpha carbon atoms of the tip amino acid of the p-loop (Gly43) and the starting amino acid of the C helix (Ser46) before and after pulling are 14.15 Å and 7.23 Å, respectively.<ref name="premier">doi:10.1007/s00894-009-0629-4</ref>
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