STI571 Binding to c-Kit and PDGFR

An understanding of the molecular interactions at the atomic level between STI571 and Abl was key to understand the binding mode between STI571 and the inactive conformation of c-Kit (Manley et al. 2002). Six hydrogen-bonding interactions between STI571 and c-Kit, which are found in the STI571-Abl structure, were suggested by homology modeling, and five of these were recently confirmed by analysis of the crystal structure of a complex between c-Kit and STI571 (Jacob et al. unpublished) (Fig. 2). The predicted amide-C=O interaction with D810 of the DFG motif does not occur due to a very slight twist of STI571 in binding to c-Kit compared to Abl. Assuming a similar auto-inhibitory conformation as in Abl and c-Kit, these H-bonds are also believed to be important interactions between STI571 and PDGFRb (in PDGFRa the residues interacting with STI571 are identical) (Fig. 2).

The interactions comprise:

1. Anilino-NH with T670 (T315 in Abl and T681 in PDGFRb).

2. Amide-NH with E640 (E286 in Abl and E651 in PDGFRb).

3. Amide-C=O with D810 of the DFG motif does not occur in c-Kit (occurs in Abl with D381, and possibly in PDGFRb with D844).

4. Pyridine-N with C673 (M318 in Abl and C684 in PDGFRb).

5. N-methylpiperazine with I360 and H361 (I789/H790in Abl and I823/H824 in PDGFRb).

Interestingly, STI571 is inactive against the activating mutations found in systemic mastocytosis, seminoma, and AML that affect position D816 (Heinrich et al. 2002). Mutations in D816, which lies four amino acids beyond the DFG motif in the A-loop, appear to disfavor the auto-inhibitory conformation of the A-loop such that STI571 does not bind.

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