8JOT

Crystal structure of CSF-1R kinase domain with sulfatinib

Summary for 8JOT

• Entry DOI: 10.2210/pdb8jot/pdb
• Descriptor: Macrophage colony-stimulating factor 1 receptor, N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidin-2-yl)amino)phenyl)methanesulfonamide, GLYCEROL, ... (4 entities in total)
• Functional Keywords: sulfatinib, fgfr1, dfg-out, transferase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 40513.33

Authors

Lin, Q.M.,Chen, X.J.,Chen, Y.H. (deposition date: 2023-06-08, release date: 2024-03-27)

Primary citation

Lin, Q.,Dai, S.,Qu, L.,Lin, H.,Guo, M.,Wei, H.,Chen, Y.,Chen, X.
Structural basis and selectivity of sulfatinib binding to FGFR and CSF-1R.
Commun Chem, 7:3-3, 2024

PubMed Abstract: Acquired drug resistance poses a challenge for single-target FGFR inhibitors, leading to the development of dual- or multi-target FGFR inhibitors. Sulfatinib is a multi-target kinase inhibitor for treating neuroendocrine tumors, selectively targeting FGFR1/CSF-1R. To elucidate the molecular mechanisms behind its binding and kinase selectivity, we determined the crystal structures of sulfatinib with FGFR1/CSF-1R. The results reveal common structural features and distinct conformational adaptability of sulfatinib in response to FGFR1/CSF-1R binding. Further biochemical and structural analyses disclose sensitivity of sulfatinib to FGFR/CSF-1R gatekeeper mutations. The insensitivity of sulfatinib to FGFR gatekeeper mutations highlights the indispensable interactions with the hydrophobic pocket for FGFR selectivity, whereas the rotatory flexibility may enable sulfatinib to overcome CSF-1R. This study not only sheds light on the structural basis governing sulfatinib's FGFR/CSF-1R inhibition, but also provides valuable insights into the rational design of dual- or multi-target FGFR inhibitors with selectivity for CSF-1R and sensitivity to gatekeeper mutations.

PubMed: 38172256
DOI: 10.1038/s42004-023-01084-0

Experimental method

X-RAY DIFFRACTION (1.69 Å)