7WCL

Crystal structure of FGFR1 kinase domain with Pemigatinib

7WCL の概要

• エントリーDOI: 10.2210/pdb7wcl/pdb
• 分子名称: 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)
• 機能のキーワード: kinase, inhibitor, complex, structural protein, transferase-transferase inhibitor complex, tra, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 72080.42

構造登録者

Chen, X.J.,Lin, Q.M.,Jiang, L.Y.,Qu, L.Z.,Chen, Y.H. (登録日: 2021-12-20, 公開日: 2022-09-14, 最終更新日: 2023-11-29)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.495 Å)