Crystal Structure of the FGFR4/LY2874455 Complex Reveals Insights into the Pan-FGFR Selectivity of LY2874455.
Crystal Structure of the FGFR4/LY2874455 Complex Reveals Insights into the Pan-FGFR Selectivity of LY2874455.
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DOI：
10.1371/journal.pone.0162491
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Chen Y
中科院分区：
文献类型：
--
作者：
Wu D;Guo M;Philips MA;Qu L;Jiang L;Li J;Chen X;Chen Z;Chen L;Chen Y
FGFR4信号通路的异常在多种人类癌症中都有大量的文献记载。与FGFR1-3相比，大多数FGFR抑制剂对FGFR4的抑制作用显著降低。而LY2874455对FGFR1-4有相似的抑制作用，IC50小于6.4 nM。到目前为止，还没有文献报道LY2874455与任何一种激酶形成的复合体的晶体结构。为了更好地了解LY2874455的PAN-FGFR选择性，我们测定了与LY2874455结合的FGFR4激酶结构域的晶体结构。LY2874455是FGFR4的I型抑制剂，以DFG-活性构象与FGFR4的ATP结合口袋结合，具有三个氢键和多个van der Waals接触。我们的结构分析表明，LY2874455与FGFR4的相互作用在很大程度上是保守的，这至少部分解释了LY2874455对4个FGFR的广泛抑制活性。因此，我们的研究揭示了对LY2874455的泛FGFR选择性的新见解，并为开发广泛靶向FGFR1-4的新型FGFR抑制剂提供了结构基础。
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.
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DOI：
10.3390/diseases3040294
发表时间：
2015-10-28
期刊：
Diseases (Basel, Switzerland)
影响因子：
--
作者：
Repana D;Ross P
通讯作者：
Ross P
影响因子：
11.5
作者：
Brooks, A. Nigel;Kilgour, Elaine;Smith, Paul D.
通讯作者：
Smith, Paul D.
影响因子：
14.8
作者：
Liu, Y;Gray, NS
通讯作者：
Gray, NS
影响因子：
5.7
作者：
Nakanishi, Yoshito;Akiyama, Nukinori;Ishii, Nobuya
通讯作者：
Ishii, Nobuya
影响因子：
5.7
作者：
Tucker, Julie A.;Klein, Tobias;Norman, Richard A.
通讯作者：
Norman, Richard A.