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Structures of PDK1 with Bisindolylmaleimides and LY333531

Bisindolylmaleimides were also cocrystallized with PDK1 (PDB-codes 1UU7, 1UU8, 1UU9, 1UVR) (Komander et al. 2004). The structure obtained with PDK1 and BIM2 is very similar to the molecule A of our structure of PKA and BIM2, but an alternative conformation comparable to the molecule B structure of PKA with BIM2 was not observed in the case of PDK1. The hinge region contacts of the bisindolylmaleimides are conserved between the two kinases. As in PKA, BIM2 in PDK1 also shows the inwards rotation of the untethered indole. As one of the rare AGC kinase without a comparable residue to Phe327, the PDK1 structure also lacks these contacts between the inhibitor and the kinase, in this respect similar to the structure of PKA, where the corresponding peptide stretch is mobile and not resolved. As a striking difference between the two BIM2 kinase complexes, the glycine-rich loop in PDK1 shows no conformational change similar to that in PKA, and no contact between the Phe54 homologue in PDK1 is made to the pyrroli-dine-attached methyl group of BIM2. A possible reason is the exchange of Gly52 (PKA) to serine in PDK1, which reduces the flexibility of the glycine flap and might cause steric problems. As in the less-pronounced case of the Phe54 interaction with the staurosporine sugar methyl group in PKA, where other kinases that possess the corresponding residue and still do not make the contact, the real reasons for the presence or absence of this interaction may be different.

The presence of a PKA molecule which contains an upsidedown-oriented BIM2 inhibitor, in contrast to PDK1, may be facilitated by Pro124 in PKA. In the B molecule in PKA, BIM2 is wedged between Val57 from the N-lobe, and Pro124, which makes one-sixth of all VDW contacts to the inhibitor.

Atp Camp Tesmer
Fig. 15 Stereo representation of LY333531 interactions within the ATP binding pocket of PDK1. Ligand carbon atoms are in dark grey and protein carbon atoms in light grey. Hydrogen bonds are indicated by black dotted lines. A grey ribbon indicates the protein backbone. (Komander et al. 2004)

The corresponding residue is a lysine in PDK1, which would not be suitable for similar interactions.

Another PKC inhibitor of the bisindolylmaleimide class, LY333531 or ruboxistaurin, has also been cocrystallized in complex with PDK1 (PDB-code 1UU3) (Komander et al. 2004) (Fig. 15). LY333531 shows PKC isoform specificity (e.g. 80- and 60-fold selectivity for PKQ3I and PKQ3II over PKCa (Jirousek et al. 1996) and is in phase III clinical trials for diabetic retinopathy and diabetic macular oedema (Frank 2002 and citations therein). LY333531 shares much of the flexibility of BIM2, except that the cyclic connection of both N-atoms of the indoles with a 6-atom ether linker prevents a comparable inwards rotation of one indole as seen with bisindolylmaleimide 2 (Fig. 12). Komander et al. explain the higher binding affinity of inhibitors such as staurosporine, UCN01 and LY333531 in contrast to bisindolyl-maleimides by a preference of PDK1 for carbon atoms at specific positions which are satisfied by the indolocarbazoles and LY333531 but not by the bisindolylmaleimides. Mutagenesis of PDK1 and sequence comparisons, however, did not explain the selectivity of the bisindolylmaleimides and LY333531 for the PKC isoforms.

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