Table 1.
Data collection and refinement statistics.
Figure 1.
Structure of c-Src in complex with Ruxolitinib.
(A) Overall structure of c-Src/Ruxolitinib complex. (B) The pyrrolopyrimidine rings form two hydrogen bonds with the main chain atoms of Met341. (C) Ruxolitinib forms a water-mediated interaction with Src gatekeeper residue Thr338.
Figure 2.
(A) active Lck DFG-in conformation (pdb: 3LCK); (B) active c-Src T338I DFG-in conformation (pdb: 3DQW); (C) active c-Src DFG-in conformation in Src/Ruxolitinib complex (this work); (D) inactive c-Src in the Src/CDK conformation, DFG-intermediate (pdb: 2SRC); (E) inactive c-Src DFG-out conformation in Src/Imatinib complex (pdb: 2OIQ).
Figure 3.
Comparison of pocket occupancy between c-Src/Imatinib and c-Src/Ruxolitinib structures.
(A) Pocket occupancy of Imatinib in the c-Src/Imatinib complex (pdb: 2OIQ). C-Src structure is shown in cartoon, colored in magenta. Imatinib is shown in sphere. (B) Pocket occupancy of Ruxolitinib in the c-Src/Ruxolitinib complex (this work). C-Src structure is shown in cartoon, colored in yellow. Ruxolitinib is shown in sphere.
Figure 4.
Sequence alignment of LCK, HCK, c-SRC, JAK1, JAK2 and JAK3 kinase domains.
The conserved DFG motif is highlighted in blue box; the gatekeeper residue is highlighted in red box; residue corresponding to Met341 in c-Src is highlighted in purple box; several extra stretches of amino acids are highlighted in green box.
Figure 5.
Structure comparison of c-Src and JAK1 structures.
(A) c-Src kinase domain (this work) is superimposed with JAK1 kinase domain (pdb: 3EYG) using the Ca atoms of kinase domain as the reference. c-Src is shown yellow, while JAK1 is shown in magenta. (B) Predicted c-Src ligand-binding pocket is shown in grey dots. (C) Predicted JAK1 ligand-binding pocket is shown in grey dots. Ligand-binding pocket is predicted using POCASA[30].
Figure 6.
Docking of Ruxolitinib in JAK1 kinase domain.
(A) Ruxolitinib was docked into the ligand-binding pocket of JAK1 (pdb: 3EYG). JAK1 kinase domain is shown in cartoon, and colored in magenta. Ruxilitinib is shown in sphere. (B) Predicted hydrogen bonds between Ruxolitinib and JAK1 hinge region. Based on docking result, the pyrrolopyrimidine rings of Ruxolitinib form two hydrogen bonds with JAK1 Glu957 and Leu959. (C) Shape complementarity between Ruxolitinib and JAK1 ligand-binding pocket. (D) Shape complementarity between Ruxolitinib and c-Src ligand-binding pocket. The predicted ligand-binding pocket is shown in grey mesh.