Figure 4

Structural basis for SB-203580 selectivity. The 3D structure of Abl (PDB 1M52, wire rendering with grey carbons) was superposed onto the structure of p38 (hidden) in complex with SB-203580 (PDB 1A9U, ball and stick rendering with green carbons). Like p38, Abl has a Thr at the gatekeeper position and suggests that there are other selectivity determinants that prevent SB-203580 from inhibiting Abl. The fluorophenyl of SB-203580 appears to clash (orange lines) with Ile 313 (ball and stick rendering with grey carbons) of Abl. In contrast, Leu 104 (stick rendering with green carbons) of p38 accommodates the compound. Importantly, the isoleucine is deep in the pocket where other isoleucine rotamers are likely to clash with other residues in Abl. Based on this putative steric clash, we propose that S-Filter correctly predicted Leu 104 as specificity determinant for Roscovitine.