7WCL

Crystal structure of FGFR1 kinase domain with Pemigatinib

Summary for 7WCL

• Entry DOI: 10.2210/pdb7wcl/pdb
• Descriptor: Fibroblast growth factor receptor 1, 11-[2,6-bis(fluoranyl)-3,5-dimethoxy-phenyl]-13-ethyl-4-(morpholin-4-ylmethyl)-5,7,11,13-tetrazatricyclo[7.4.0.0^{2,6}]trideca-1(9),2(6),3,7-tetraen-12-one, SULFATE ION, ... (4 entities in total)
• Functional Keywords: kinase, inhibitor, complex, structural protein, transferase-transferase inhibitor complex, tra, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 72080.42

Authors

Chen, X.J.,Lin, Q.M.,Jiang, L.Y.,Qu, L.Z.,Chen, Y.H. (deposition date: 2021-12-20, release date: 2022-09-14, Last modification date: 2023-11-29)

Primary citation

Lin, Q.,Chen, X.,Qu, L.,Guo, M.,Wei, H.,Dai, S.,Jiang, L.,Chen, Y.
Characterization of the cholangiocarcinoma drug pemigatinib against FGFR gatekeeper mutants.
Commun Chem, 5:100-100, 2022

PubMed Abstract: Fibroblast growth factor receptor (FGFR) dysregulation is involved in a variety of tumorigenesis and development. Cholangiocarcinoma is closely related with FGFR aberrations, and pemigatinib is the first drug approved to target FGFR for the treatment of cholangiocarcinoma. Herein, we undertake biochemical and structural analysis on pemigatinib against FGFRs as well as gatekeeper mutations. The results show that pemigatinib is a potent and selective FGFR1-3 inhibitor. The extensive network of hydrogen bonds and van der Waals contacts found in the FGFR1-pemigatinib binding mode accounts for the high potency. Pemigatinib also has excellent potency against the Val-to-Ile gatekeeper mutation but less potency against the Val-to-Met/Phe gatekeeper mutation in FGFR. Taken together, the inhibitory and structural profiles exemplified by pemigatinib may help to thwart Val-to-Ile gatekeeper mutation-based resistance at earlier administration and to advance the further design and improvement for inhibitors toward FGFRs with gatekeeper mutations.

PubMed: 36698015
DOI: 10.1038/s42004-022-00718-z

Experimental method

X-RAY DIFFRACTION (2.495 Å)