Crystal Structure of the FGFR4/LY2874455 Complex Reveals Insights into the Pan-FGFR Selectivity of LY2874455.
Aberrant FGFR4 signaling has been documented abundantly in various human cancers. The majority of FGFR inhibitors display significantly reduced potency toward FGFR4 compared to FGFR1-3. However, LY2874455 has similar inhibition potency for FGFR1-4 with IC50 less than 6.4 nM. To date, there is no published crystal structure of LY2874455 in complex with any kinase. To better understand the pan-FGFR selectivity of LY2874455, we have determined the crystal structure of the FGFR4 kinase domain bound to LY2874455 at a resolution of 2.35 Å. LY2874455, a type I inhibitor for FGFR4, binds to the ATP-binding pocket of FGFR4 in a DFG-in active conformation with three hydrogen bonds and a number of van der Waals contacts. After alignment of the kinase domain sequence of 4 FGFRs, and superposition of the ATP binding pocket of 4 FGFRs, our structural analyses reveal that the interactions of LY2874455 to FGFR4 are largely conserved in 4 FGFRs, explaining at least partly, the broad inhibitory activity of LY2874455 toward 4 FGFRs. Consequently, our studies reveal new insights into the pan-FGFR selectivity of LY2874455 and provide a structural basis for developing novel FGFR inhibitors that target FGFR1-4 broadly.
Laboratory of Structural Biology, Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, XiangYa Hospital, Central South University, Changsha, Hunan 410008, China.
Daichao
D
Wu
Laboratory of Structural Biology, Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, XiangYa Hospital, Central South University, Changsha, Hunan 410008, China.
Ming
M
Guo
Molecular and Computational Biology, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, United States of America.
Michael A
MA
Philips
Laboratory of Structural Biology, Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, XiangYa Hospital, Central South University, Changsha, Hunan 410008, China.
Lingzhi
L
Qu
Laboratory of Structural Biology, Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, XiangYa Hospital, Central South University, Changsha, Hunan 410008, China.
Longying
L
Jiang
Laboratory of Structural Biology, Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, XiangYa Hospital, Central South University, Changsha, Hunan 410008, China.
Jun
J
Li
Laboratory of Structural Biology, Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, XiangYa Hospital, Central South University, Changsha, Hunan 410008, China.
Xiaojuan
X
Chen
Laboratory of Structural Biology, Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, XiangYa Hospital, Central South University, Changsha, Hunan 410008, China.
Zhuchu
Z
Chen
Laboratory of Structural Biology, Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, XiangYa Hospital, Central South University, Changsha, Hunan 410008, China.|Molecular and Computational Biology, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, United States of America.
Lin
L
Chen
Laboratory of Structural Biology, Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, XiangYa Hospital, Central South University, Changsha, Hunan 410008, China.|Molecular and Computational Biology, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, United States of America.|Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, Guangdong, China.
Yongheng
Y
Chen
D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D003460:Crystallization; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D007191:Indazoles / Q000737:chemistry / Q000378:metabolism*; D015394:Molecular Structure; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000737:chemistry / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
C570663:2-(4-(2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3yl)vinyl)-1H-pyrazol-1-yl)ethanol; D007191:Indazoles; D000255:Adenosine Triphosphate; C496371:FGFR4 protein, human; D051499:Receptor, Fibroblast Growth Factor, Type 4