The Free Energy Profile of Tubulin Straight-Bent Conformational Changes, with Implications for Microtubule Assembly and Drug Discovery
Figure 3
The (a) probability distribution, (b) free energy profile, and (c) buried surface area of unpolymerized tubulin as a function of intradimer curvature.
Intradimer rotation of the endpoint structures, the straight taxol-liganded, zinc-stabilized protofilament tubulin and bent α1β1 heterodimer from the T2R-colchicine complex, are denoted at θ = 0° (blue dash) and θ∼12° (red dash), respectively. Intradimer rotation of selected intermediately bent tubulins are denoted as dotted lines: θ∼5° (GMPCPP-tubulin in double-tube layers), θ∼6° (α2β2 heterodimer of the T2R-TTL-ADP, T2R-TTL-zampanolide, and T2R-TTL complexes), θ∼6.9° (both α1β1 and α2β2 heterodimers of the GTP-tubulin-D1 DARPin structure), and θ∼10° (α1β1 heterodimer of T2R-TTL-zampanolide and T2R-TTL epothilone A complexes). Buried surface area values of tubulin heterodimer structures with resolutions up to 3 Å are shown in panel (c); the structures from PMF in (b) (open circles) and crystal structures of the straight (solid triangle) and bent (solid circles) heterodimers are denoted for each tubulin complex.