Figure 6.

Binding of compound 3 to TTBK1. (a) Two-dimensional representation of compound 3 oriented similarly to that in (b). An IUPAC name for compound 3 is 3-({5-[(4-amino-4-methylpiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-4-yl}amino)-5-bromophenol. (b) Initial F _o − F _c electron density contoured at 3 r.m.s.d. (slate) and 10 r.m.s.d. (orange) with the final model of the TTBK1–compound 3 complex. The hinge region (residues 108–111) is at the top of the figure and the gatekeeper residue (Met107) is on the right. C atoms are shown in cyan for TTBK1 and in orange for compound 3, N atoms are shown in blue, O atoms are shown in red, S atoms are shown in yellow, the Br atom is shown in violet and waters are represented by red spheres. (c) Cartoon representation of the placement of compound 3 in the context of the entire TTBK1 kinase domain, with a superposition of the apo structure on the complex structure. The complex structure is shown in cyan, the apo structure is shown in magenta and compound 3 is shown with C atoms in orange, N atoms in blue, the O atom in red and the Br atom in violet. (d) Superposition of the apo structure at the binding site on the structure of the complex with compound 3. The hinge region (residues 108–111) is at the top of the figure. C atoms are shown in cyan for the complex structure and magenta for the apo structure, N atoms are shown in blue, O atoms are shown in red, S atoms are shown in yellow, the Br atom is shown in violet and water molecules are shown as red spheres. Hydrogen bonds are shown as a series of black prolate ellipsoids. The figures show that only the side chains of Glu77, Met107 (gatekeeper residue) and to a lesser extent Asp176 move significantly upon binding compound 3.