Structural basis for GW-572016. The 3D structure of p38 (PDB 1A9U, wire rendering with grey carbons) was superposed onto the structure of EGFR (hidden) in complex with GW-572016 (PDB 1XKK, ball and stick rendering with green carbons). GW-572016 appears to clash (orange lines) with Ile 84 (ball and stick rendering with grey carbons) of p38. In contrast, Cys 775 (stick rendering with green carbons) of EGFR accommodates the compound. Importantly, Ile 84 is buried deep in the protein where there is little room to maneuver and clearly protrudes the pocket (mustard) of EGFR. Based on this putative steric clash, we propose that S-Filter correctly predicted Cys 775 as specificity determinant for GW-572016.