Target Binding Site Detail
| Target General Information | Top | ||||
|---|---|---|---|---|---|
| Target ID | T90989 | Target Info | |||
| Target Name | Fibroblast growth factor receptor 4 (FGFR4) | ||||
| Synonyms | TKF; JTK2; FGFR-4; CD334 | ||||
| Target Type | Clinical trial Target | ||||
| Gene Name | FGFR4 | ||||
| Biochemical Class | Kinase | ||||
| UniProt ID | |||||
| Ligand General Information | Top | ||||
|---|---|---|---|---|---|
| Ligand Name | LY2874455 | Ligand Info | |||
| Canonical SMILES | CC(C1=C(C=NC=C1Cl)Cl)OC2=CC3=C(C=C2)NN=C3C=CC4=CN(N=C4)CCO | ||||
| InChI | 1S/C21H19Cl2N5O2/c1-13(21-17(22)10-24-11-18(21)23)30-15-3-5-20-16(8-15)19(26-27-20)4-2-14-9-25-28(12-14)6-7-29/h2-5,8-13,29H,6-7H2,1H3,(H,26,27)/b4-2+/t13-/m1/s1 | ||||
| InChIKey | GKJCVYLDJWTWQU-CXLRFSCWSA-N | ||||
| PubChem Compound ID | 46944259 | ||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| PDB ID: 5JKG The crystal structure of FGFR4 kinase domain in complex with LY2874455 | ||||||
| Method | X-ray diffraction | Resolution | 2.35 Å | Mutation | No | [1] |
| PDB Sequence |
DLPLDPLWEF
462 PRDRLVLGKP472 LGEGAFGQVV482 RAEAFGMDPA492 RPDQASTVAV502 KMLKDDKDLA 515 DLVSEMEVMK525 LIGRHKNIIN535 LLGVCTQEGP545 LYVIVECAAK555 GNLREFLRAR 565 RPPGPPLSFP587 VLVSCAYQVA597 RGMQYLESRK607 CIHRDLAARN617 VLVTEDNVMK 627 IADFGLLPVK654 WMAPEALFDR664 VYTHQSDVWS674 FGILLWEIFT684 LGGSPYPGIP 694 VEELFSLLRE704 GHRMDRPPHC714 PPELYGLMRE724 CWHAAPSQRP734 TFKQLVEALD 744 KVLLAV
|
|||||
|
|
LEU473
2.957
GLY474
3.999
GLU475
3.247
GLY476
4.274
VAL481
3.925
ARG483
4.211
ALA501
3.605
LYS503
4.017
ILE534
3.936
VAL550
3.994
GLU551
2.746
|
|||||
| PDB ID: 5XFF Crystal structure of LY2874455 in complex of FGFR4 gatekeeper mutation (V550L) | ||||||
| Method | X-ray diffraction | Resolution | 2.70 Å | Mutation | Yes | [2] |
| PDB Sequence |
DLPLDPLWEF
462 PRDRLVLGKP472 LGEGAFGQVV482 RAEAFGMDPA492 RPDQASTVAV502 KMLKDNASDK 512 DLADLVSEME522 VMKLIGRHKN532 IINLLGVCTQ542 EGPLYVILEC552 AAKGNLREFL 562 RARRPPGPPL584 SFPVLVSCAY594 QVARGMQYLE604 SRKCIHRDLA614 ARNVLVTEDN 624 VMKIADFGLL651 PVKWMAPEAL661 FDRVYTHQSD671 VWSFGILLWE681 IFTLGGSPYP 691 GIPVEELFSL701 LREGHRMDRP711 PHCPPELYGL721 MRECWHAAPS731 QRPTFKQLVE 741 ALDKVLLAV
|
|||||
|
|
LEU473
3.287
GLY474
3.826
GLU475
3.913
GLY476
4.656
VAL481
3.780
ALA501
3.622
LYS503
4.089
ILE534
4.344
LEU550
4.400
GLU551
3.008
CYS552
3.617
|
|||||
| PDB ID: 5XFJ Crystal structure of LY2874455 in complex of FGFR4 gatekeeper mutation (V550M) | ||||||
| Method | X-ray diffraction | Resolution | 3.25 Å | Mutation | Yes | [2] |
| PDB Sequence |
DLPLDPLWEF
462 PRDRLVLGKP472 LGEGAFGQVV482 RAEAFGMDPA492 RPDQASTVAV502 KMLKDDKDLA 515 DLVSEMEVMK525 LIGRHKNIIN535 LLGVCTQEGP545 LYVIMECAAK555 GNLREFLRAR 565 RPPGPPLSFP587 VLVSCAYQVA597 RGMQYLESRK607 CIHRDLAARN617 VLVTEDNVMK 627 IADFGLLPVK654 WMAPEALFDR664 VYTHQSDVWS674 FGILLWEIFT684 LGGSPYPGIP 694 VEELFSLLRE704 GHRMDRPPHC714 PPELYGLMRE724 CWHAAPSQRP734 TFKQLVEALD 744 KVLLAV
|
|||||
|
|
LEU473
2.993
GLY474
4.390
GLU475
3.138
GLY476
4.355
VAL481
3.755
ALA501
3.584
LYS503
3.576
ILE534
4.407
MET550
4.807
GLU551
3.261
CYS552
3.658
|
|||||
| References | Top | ||||
|---|---|---|---|---|---|
| REF 1 | Crystal Structure of the FGFR4/LY2874455 Complex Reveals Insights into the Pan-FGFR Selectivity of LY2874455. PLoS One. 2016 Sep 12;11(9):e0162491. | ||||
| REF 2 | LY2874455 potently inhibits FGFR gatekeeper mutants and overcomes mutation-based resistance. Chem Commun (Camb). 2018 Oct 23;54(85):12089-12092. | ||||
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