Figure 1.
The discrepancy between the average structures of apo and compound-3 bound complexes.
(A) Comparison of PTP1B in the allosteric inhibitor bound state and apo state by superimposing the average structures. The whole structures fit well (shown in silver), excepting certain regions undergoing marked rearrangements (inhibitor bound state–cyan; apo state–red). Active sites and allosteric sites are shown as spheres. The allosteric site is located ∼20 Å away from the active site. (B) Projection of the WPD loop on the first two eigenvectors, denoted with PC1 and PC2. Red and blue dots represent samples from the apo and compound-3 bound state MD simulations, respectively. (C) A time evolution of the RMSD was performed on the WPD loop in the apo state (red), compound-3 bound state (blue) and substrate bound state (black) simulations with reference to their respective initial structures. (D) The Cα distances between Gly183 and Gly220 among the three MD simulations.
Figure 2.
Dynamic community analysis of both the apo and compound-3 bound PTP1B.
(A) Structural domains matching up to their communities are highlighted in consistent colors. Notable structural elements are also shown on the protein structure. (B) Visualization of the correlation coefficient matrix based on the MD trajectories for the compound-3-minus-apo PTP1B complexes. Note, dramatic changes have taken place in the correction of the magenta box between C7 (helix α7) and C4. (C) and (D). Color coded optimal community network of the apo and compound-3 bound state with ball-and-stick models. Each ball stands for an individual community. The stick stands for the “betweeness”. Color scheme: C1, C1’(gold); C2, C2’(purple); C3, C3’(cyan); C4, C4’(red); C5, C5’(green); C6, C6’(pink); and C7, C7’(magenta). C3 (C3’) stands for the C-node of helix α3. C4 (C4’) stands for the WPD loop and N-terminal helix α3. C7 stands for helix α7. The partial region of C1’ (C1), C2 (C2’) and C4’ (C4) form the active site. The allosteric site consists of parts of C3’ (C3), C6’ (C6) and C7’ (C7).
Figure 3.
Conformational rearrangements in the conservative WPD domain for both states.
(A) Comparison of the region between the WPD loop and R loop in the apo state (red) and compound-3 bound state (cyan). (B) The distance between the OE atom in Glu115 and OD atom in Asp181 (top) and the distance of the side chains between Trp179 and Arg221 (bottom) were monitored in the apo state (red) and compound-3 bound state (blue). (C) and (D)View of the hydrophobic environment of the WPD loop in the apo state (red) and the compound-3 bound state (cyan). (E) View of the indole ring of Trp179 in the apo state (red) and the compound-3 bound state (cyan).
Figure 4.
Structural reconstruction of the dynamic interactions for helix α7 with helix α3.
(A) Comparison of the distance between Arg221 and Ser190 in the apo (red) and compound-3 bound state (cyan). (B) Tracing the distance between Ser190 and Arg221 in in the apo (red) and the compound-3 bound state (blue). (C) and (D) View of the triangular interactional region among N-terminal helix α3, helix α7, loop 11 in the apo (red) and the new interactional interfaces between helix α7 and helix α3 after compound-3 bound (cyan). (E) The results of Define Secondary Structure of Proteins (DSSP) [52] derived from the PTRAJ module show that the N-terminal helix α7 (residue 285–291) uncoils in the compound-3 bound state (bottom).
Figure 5.
The allosteric signal pathway for PTP1B propagating from the allosteric to the active site.