CDK2

CDK2 has two domains, a small (85 residue) amino-terminal domain comprising a single a helix and a five-stranded p sheet and a larger (213 residues) domain that is mainly a-helical (Figure 6.17a). The cofactor in the... 

In free CDK2 the active site cleft is blocked by the T-loop and Thr 160 is buried (Figure 6.20a). Substrates cannot bind and Thr 160 cannot be phosphorylated consequently free CDK2 is inactive. The conformational changes induced by cyclin A binding not only expose the active site cleft so that ATP and protein substrates can bind but also rearrange essential active site residues to make the enzyme catalytically competent (Figure 6.20b). In addition Thr... 

Figure 6.18 The PSTAIRE helix undergoes a major conformational change when CDK2 binds to cyclin A. In the inactive free CDK2 (yellow) the active site residue Glu 51 is far from the active site. Upon binding of cyclin A to CDK2 the PSTAIRE helix (hiue) rotates 90° and changes its position so that Glu 51 becomes positioned into the active site. (Adapted from P.D. Jeffry et al.. Nature 376 313-320, 1995.)...

Figure 6.20 Space-filling diagram illustrating the structural changes of CDK2 upon cyclin binding, (a) The active site is in a cleft between the N-terminal domain (blue) and the C-terminal domain (purple). In the inactive form this site is blocked by the T-loop.

Radzio-Andzelm, E.R., Few, J., Taylor, S. Bound to activate conformational consequences of cyclin binding to CDK2. Structure 3 1135-1141, 1995. 

Jeffrey, P.D., et al. Mechanism of CDK activation revealed by the structure of a cyclinA-CDK2 complex. Nature 376 31.3-320, 1995. 

A number of kinase structures have been determined in various catalytic states. For example, structures of the cyclin-dependent kinase, CDK2, in its inactive state and in a partially active state after cyclin binding have been discussed in Chapter 6. The most thoroughly studied kinase is the cyclic AMP-dependent protein kinase the structure of both the inactive and the active... 

Othet cyclins and CDKs are involved in different aspects of cell cycle progression (Table 36-7). Cychn E and CDK2 form a complex in late Gl. Cychn E is tapidly degraded, and the released CDK2 then fotms a complex with cyclin A. This sequence is necessaty fot the initiation of DNA synthesis in S phase. A complex between cychn B and CDKl is tate-hmiting fot the G2/M transition in eukatyotic cells. 

Fig. 1.10 Cdk2 inhibitor identified using NMR screening by the WaterLOGSY method.

There are many functions available and, as stated above, their performance can vary hugely across different receptors. So which combination is best suited to the target of interest Lyne et al. [95] used a consensus scheme derived from a previous study of Cdk2. A database of 8,000 compounds... 

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