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 | Ponatinib | Ligand Info | |||
| Canonical SMILES | CC1=C(C=C(C=C1)C(=O)NC2=CC(=C(C=C2)CN3CCN(CC3)C)C(F)(F)F)C#CC4=CN=C5N4N=CC=C5 | ||||
| InChI | 1S/C29H27F3N6O/c1-20-5-6-22(16-21(20)8-10-25-18-33-27-4-3-11-34-38(25)27)28(39)35-24-9-7-23(26(17-24)29(30,31)32)19-37-14-12-36(2)13-15-37/h3-7,9,11,16-18H,12-15,19H2,1-2H3,(H,35,39) | ||||
| InChIKey | PHXJVRSECIGDHY-UHFFFAOYSA-N | ||||
| PubChem Compound ID | 24826799 | ||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| PDB ID: 4QRC Crystal Structure of the Tyrosine Kinase Domain of FGF Receptor 4 in Complex with Ponatinib | ||||||
| Method | X-ray diffraction | Resolution | 1.90 Å | Mutation | Yes | [1] |
| PDB Sequence |
LPLDPLWEFP
463 RDRLVLGKPL473 GEGAFGQVVR483 AEAFGMDPAR493 PDQASTVAVK503 MLKDNASDKD 513 LADLVSEMEV523 MKLIGRHKNI533 INLLGVCTQE543 GPLYVIVECA553 AKGNLREFLR 563 ARRPPGPDLS573 PDGPRSSEGP583 LSFPVLVSCA593 YQVARGMQYL603 ESRKCIHRDL 613 AARNVLVTED623 NVMKIADFGL633 ARGVHHIDYY643 KKTSNGRLPV653 KWMAPEALFD 663 EVYTHQSDVW673 SFGILLWEIF683 TLGGSPYPGI693 PVEELFSLLR703 EGHRMDRPPH 713 CPPELYGLMR723 ECWHAAPSQR733 PTFKQLVEAL743 DKVLLAV
|
|||||
|
|
LEU473
3.881
VAL481
3.491
ALA501
3.517
VAL502
3.646
LYS503
3.322
GLU520
2.613
VAL523
4.196
MET524
3.465
ILE527
4.597
ILE533
4.588
ILE534
3.942
VAL548
4.199
VAL550
3.255
GLU551
3.026
CYS552
3.377
|
|||||
| PDB ID: 4TYJ Structural analysis of the human Fibroblast Growth Factor Receptor 4 Kinase | ||||||
| Method | X-ray diffraction | Resolution | 2.45 Å | Mutation | No | [2] |
| PDB Sequence |
MGSAGLVSLD
453 LPLDPLWEFP463 RDRLVLGKPL473 GEGGQVVRAE485 AFGMDPARPD495 QASTVAVKML 505 KDNASDKDLA515 DLVSEMEVMK525 LIGRHKNIIN535 LLGVCTQEGP545 LYVIVECAAK 555 GNLREFLRAR565 RPPLSFPVLV590 SCAYQVARGM600 QYLESRKCIH610 RDLAARNVLV 620 TEDNVMKIAD630 FGLARLPVKW655 MAPEALFDRV665 YTHQSDVWSF675 GILLWEIFTL 685 GGSPYPGIPV695 EELFSLLREG705 HRMDRPPHCP715 PELYGLMREC725 WHAAPSQRPT 735 FKQLVEALDK745 VLLAVSEE
|
|||||
|
|
LEU473
3.891
GLY474
4.802
VAL481
3.912
ALA501
3.413
VAL502
3.779
LYS503
3.346
GLU520
3.043
VAL523
4.066
MET524
3.262
ILE527
3.249
ILE533
3.544
ILE534
4.015
VAL548
3.796
VAL550
3.360
|
|||||
| PDB ID: 4UXQ FGFR4 in complex with Ponatinib | ||||||
| Method | X-ray diffraction | Resolution | 1.85 Å | Mutation | Yes | [3] |
| PDB Sequence |
LDLPLDPLWE
461 FPRDRLVLGK471 PLGEGAFGQV481 VRAEAFGMDP491 ARPDQASTVA501 VKMLKDNASD 511 KDLADLVSEM521 EVMKLIGRHK531 NIINLLGVCT541 QEGPLYVIVE551 CAAKGNLREF 561 LRARRPPGPL584 SFPVLVSCAY594 QVARGMQYLE604 SRKCIHRDLA614 ARNVLVTEDN 624 VMKIADFGLA634 RGVHHIDYYK644 KTSNGRLPVK654 WMAPEALFDR664 VYTHQSDVWS 674 FGILLWEIFT684 LGGSPYPGIP694 VEELFSLLRE704 GHRMDRPPHC714 PPELYGLMRE 724 CWHAAPSQRP734 TFKQLVEALD744 KVLLAV
|
|||||
|
|
LEU473
3.668
VAL481
3.709
ALA501
3.362
VAL502
3.879
LYS503
3.520
GLU520
3.387
VAL523
4.033
MET524
3.300
ILE527
3.410
ILE533
4.763
ILE534
3.580
VAL548
3.848
VAL550
3.483
GLU551
3.549
|
|||||
| References | Top | ||||
|---|---|---|---|---|---|
| REF 1 | DFG-out mode of inhibition by an irreversible type-1 inhibitor capable of overcoming gate-keeper mutations in FGF receptors. ACS Chem Biol. 2015 Jan 16;10(1):299-309. | ||||
| REF 2 | Structural analysis of the human fibroblast growth factor receptor 4 kinase. J Mol Biol. 2014 Nov 11;426(22):3744-3756. | ||||
| REF 3 | Structural insights into FGFR kinase isoform selectivity: diverse binding modes of AZD4547 and ponatinib in complex with FGFR1 and FGFR4. Structure. 2014 Dec 2;22(12):1764-1774. | ||||
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