Figure 1.
Structures of active CDKs and imidazole inhibitors.
(A) CDK2/cyclinE complex, (B) CDK5/p25 complex, (C) cis-OH or cis-N-acetyl inhibitor, and (D) trans-OH inhibitor. In (A) and (B), CDKs are shown in green and the activators are shown in cyan. The functionally relevant regions of CDKs are highlighted: G-loop (red), PSTAIRE/PSAALRE helix (magenta), T-loop (blue), α-D helix (pink), 40s (yellow), 70s loop (orange), and CMGC conserved kinase domain (purple). The CDK2/CDK5 variant residues in substrate binding pocket are shown in licorice.
Table 1.
Reported IC50 values of the selected inhibitors in nM.
Figure 2.
B-factors of CDKs bound with cis-OH (black) and trans-OH (red) inhibitors.
Results are shown for (A) CDK2 and (B) CDK5 complexes. Highly fluctuating regions are labelled: (a) G-loop, (b) 40s loop (c) PSTAIRE helix, (d) 70s loop, (e) α-D helix, (f) substrate binding pocket, (g) T-loop, and (h) CMGC domain.
Figure 3.
Average structures of the cis/trans-OH bound CDK complexes.
For clarity, only the inhibitors and the adjacent protein residues are shown: (A) cis-OH bound CDK2, (B) trans-OH bound CDK2, (C) cis-OH bound CDK5, and (D) trans-OH bound CDK5. Possible modes of interactions are indicated by dotted lines with average distances shown. Color scheme: O: red; N: blue; protein C: cyan; inhibitor C: yellow. Hydrogens are omitted for clarity.
Figure 4.
Interaction energies between CDKs and cis/trans-OH inhibitors.
(A) CDK2 bound with cis-OH (green) and trans-OH (red); and (B) similar CDK5 complexes. Residue-level decomposition of the total energy is also included, where the significantly contributing residues are noted.
Table 2.
Free energy of binding of cis– and trans-OH inhibitors to CDKs from MMPBSA calculations.
Figure 5.
Average structures of the cis-N-acetyl bound CDK complexes.
For clarity, only the inhibitors and the adjacent protein residues are shown: (A) cis-N-acetyl bound CDK2, (B) cis-N-acetyl bound CDK5. Possible modes of interactions are indicated by dotted lines with average distances shown. Color scheme is similar to Fig. 3.
Figure 6.
Interaction energies between CDKs and cis-OH/cis-N-acetyl inhibitors.
(A) CDK2 bound with cis-OH (green) and cis-N-acetyl (red); (B) similar CDK5 complexes. Residue-level decomposition of the total energy is also included.
Figure 7.
Comparison of the interaction energies between CDK2-cis-N-acetyl (green) and CDK5-cis-N-acetyl (red) complexes.
Residue-level decomposition of the total energy is also included.
Table 3.
Free energy of binding of cis-OH and cis-N-acetyl inhibitors to CDKs from MMPBSA calculations.
Figure 8.
Electrostatic potential maps the substrate binding pocket of CDKs.
Potential maps are generated for cis-N-acetyl bound (A) CDK2 (B) CDK5 (C) CDK2:L83C mutant, and (D) CDK2:H84D mutant. Red and blue represent electronegative and electropositive potentials, respectively. The inhibitor is also shown.
Table 4.
Average solvent accessible surface area (SASA) of the substrate binding pocket of CDKs.
Figure 9.
Superimposed structures of cis-N-acetyl and roscovitine bound CDK complexes:
(A) CDK2 (B) CDK5. In roscovitine-CDK complexes, the drug and protein residues are shown in pink and grey, respectively. Remaining color scheme is similar to Fig. 3.
Figure 10.
Interaction energy of CDK5 with cis-N-acetyl (red) and roscovitine (blue).
Residue-level decomposition of the total energy is also included.
Table 5.
The contribution of electrostatic and van der Waals energy toward the total interactions in inhibitor-CDK5 complexes.