8K79
Crystal structure of c-SRC kinase domain bound by TPX-0022
Summary for 8K79
| Entry DOI | 10.2210/pdb8k79/pdb |
| Descriptor | Proto-oncogene tyrosine-protein kinase Src, Elzovantinib (3 entities in total) |
| Functional Keywords | src, tpx-0022, transferase |
| Biological source | Gallus gallus (chicken) |
| Total number of polymer chains | 2 |
| Total formula weight | 66272.12 |
| Authors | |
| Primary citation | Qu, L.,Lin, H.,Dai, S.,Guo, M.,Chen, X.,Jiang, L.,Zhang, H.,Li, M.,Liang, X.,Chen, Z.,Wei, H.,Chen, Y. Structural insight into the macrocyclic inhibitor TPX-0022 of c-Met and c-Src. Comput Struct Biotechnol J, 21:5712-5718, 2023 Cited by PubMed Abstract: c-Met has been an attractive target of prognostic and therapeutic studies in various cancers. TPX-0022 is a macrocyclic inhibitor of c-Met, c-Src and CSF1R kinases and is currently in phase I/II clinical trials in patients with advanced solid tumors harboring MET gene alterations. In this study, we determined the co-crystal structures of the c-Met/TPX-0022 and c-Src/TPX-0022 complexes to help elucidate the binding mechanism. TPX-0022 binds to the ATP pocket of c-Met and c-Src in a local minimum energy conformation and is stabilized by hydrophobic and hydrogen bond interactions. In addition, TPX-0022 exhibited potent activity against the resistance-relevant c-Met L1195F mutant and moderate activity against the c-Met G1163R, F1200I and Y1230H mutants but weak activity against the c-Met D1228N and Y1230C mutants. Overall, our study reveals the structural mechanism underlying the potency and selectivity of TPX-0022 and the ability to overcome acquire resistance mutations and provides insight into the development of selective c-Met macrocyclic inhibitors. PubMed: 38074469DOI: 10.1016/j.csbj.2023.11.028 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.8 Å) |
Structure validation
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