Target Binding Site Detail

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Target General Information
Ligand General Information
Drug Binding Sites of Target
References
Target General Information  Top
Target ID T47101 Target Info
Target Name Fibroblast growth factor receptor 1 (FGFR1)
Synonyms c-fgr; bFGF-R-1; bFGF-R; N-sam; HBGFR; Fms-like tyrosine kinase 2; FLT2; FLT-2; FLG; FGFR-1; FGFBR; CEK; CD331 antigen; CD331; Basic fibroblast growth factor receptor 1; BFGFR
Target Type Successful Target
Gene Name FGFR1
Biochemical Class Kinase
UniProt ID
FGFR1_HUMAN
Ligand General Information  Top
Ligand Name AZD4547 Ligand Info
Canonical SMILES CC1CN(CC(N1)C)C2=CC=C(C=C2)C(=O)NC3=NNC(=C3)CCC4=CC(=CC(=C4)OC)OC
InChI 1S/C26H33N5O3/c1-17-15-31(16-18(2)27-17)22-9-6-20(7-10-22)26(32)28-25-13-21(29-30-25)8-5-19-11-23(33-3)14-24(12-19)34-4/h6-7,9-14,17-18,27H,5,8,15-16H2,1-4H3,(H2,28,29,30,32)/t17-,18+
InChIKey VRQMAABPASPXMW-HDICACEKSA-N
PubChem Compound ID 51039095
Drug Binding Sites of Target  Top
PDB ID: 4RWJ      Crystal Structure of FGFR1 (C488A, C584S) in complex with AZD4547 (N-{3-[2-(3,5-DIMETHOXYPHENYL)ETHYL]-1H-PYRAZOL-5-YL}-4-[(3R,5S)-3,5-DIMETHYLPIPERAZIN-1-YL]BENZAMIDE)
Method X-ray diffraction Resolution 2.49 Å Mutation Yes [1]
PDB Sequence
MAGVSEYELP
466
EDPRWELPRD
476
RLVLGKPLGE
486
GAFGQVVLAE
496
AIGLDKDKPN
506

RVTKVAVKML
516
KSDATEKDLS
526
DLISEMEMMK
536
MIGKHKNIIN
546
LLGACTQDGP
556

LYVIVEYASK
566
GNLREYLQAR
576
RPPGLEYSYN
586
PSHNPEEQLS
596
SKDLVSCAYQ
606

VARGMEYLAS
616
KKCIHRDLAA
626
RNVLVTEDNV
636
MKIADFGLAR
646
DIHHIDYYKK
656

TNGRLPVKWM
667
APEALFDRIY
677
THQSDVWSFG
687
VLLWEIFTLG
697
GSPYPGVPVE
707

ELFKLLKEGH
717
RMDKPSNCTN
727
ELYMMMRDCW
737
HAVPSQRPTF
747
KQLVEDLDRI
757

VALTSNQ
Residue
Distance (Å)
LEU484
3.604
GLY485
3.211
PHE489
3.883
VAL492
4.232
ALA512
3.425
LYS514
3.228
LEU528
4.740
GLU531
3.429
MET535
3.831
ILE545
3.746
VAL559
3.729
VAL561
3.671
GLU562
2.972
Residue
Distance (Å)
TYR563
3.741
ALA564
3.008
SER565
3.444
LYS566
3.820
GLY567
3.332
ASN568
4.845
GLU571
3.650
LEU630
3.576
ILE639
4.790
ALA640
3.732
ASP641
2.999
PHE642
3.765
GLY643
4.982
PDB ID: 4RWK      Crystal structure of V561M FGFR1 gatekeeper mutation (C488A, C584S, V561M) in complex with N-{3-[2-(3,5-DIMETHOXYPHENYL)ETHYL]-1H-PYRAZOL-5-YL}-4-[(3R,5S)-3,5-DIMETHYLPIPERAZIN-1-YL]BENZAMIDE (AZD4547)
Method X-ray diffraction Resolution 2.98 Å Mutation Yes [1]
PDB Sequence
MAGVSEYELP
466
EDPRWELPRD
476
RLVLGKPLGE
486
GAFGQVVLAE
496
AIGLDKDKPN
506

RVTKVAVKML
516
KSDATEKDLS
526
DLISEMEMMK
536
MIGKHKNIIN
546
LLGACTQDGP
556

LYVIMEYASK
566
GNLREYLQAR
576
RPPGLEYSYN
586
PSHNPEEQLS
596
SKDLVSCAYQ
606

VARGMEYLAS
616
KKCIHRDLAA
626
RNVLVTEDNV
636
MKIADFGLAR
646
DIHHIDYYKK
656

TTNGRLPVKW
666
MAPEALFDRI
676
YTHQSDVWSF
686
GVLLWEIFTL
696
GGSPYPGVPV
706

EELFKLLKEG
716
HRMDKPSNCT
726
NELYMMMRDC
736
WHAVPSQRPT
746
FKQLVEDLDR
756

IVALTSNQ
Residue
Distance (Å)
LEU484
3.307
GLY485
4.528
GLU486
4.890
GLY490
3.364
VAL492
3.044
ALA512
3.482
LYS514
3.313
ILE545
3.830
MET561
4.038
GLU562
2.928
TYR563
3.796
Residue
Distance (Å)
ALA564
3.023
SER565
3.286
LYS566
3.880
GLY567
3.276
GLU571
3.488
ARG627
4.326
ASN628
3.590
LEU630
3.626
ALA640
4.016
ASP641
3.616
PDB ID: 4WUN      Structure of FGFR1 in complex with AZD4547 (N-{3-[2-(3,5-DIMETHOXYPHENYL)ETHYL]-1H-PYRAZOL-5-YL}-4-[(3R,5S)-3,5-DIMETHYLPIPERAZIN-1-YL]BENZAMIDE) at 1.65 angstrom
Method X-ray diffraction Resolution 1.65 Å Mutation No [2]
PDB Sequence
LPEDPRWELP
474
RDRLVLGKPL
484
GEGAFGQVVL
494
AEAIGLDKDK
504
PNRVTKVAVK
514

MLKSDATEKD
524
LSDLISEMEM
534
MKMIGKHKNI
544
INLLGACTQD
554
GPLYVIVEYA
564

SKGNLREYLQ
574
ARRPPLEYSY
585
NPSHNPEEQL
595
SSKDLVSCAY
605
QVARGMEYLA
615

SKKCIHRDLA
625
ARNVLVTEDN
635
VMKIADFGLP
663
VKWMAPEALF
673
DRIYTHQSDV
683

WSFGVLLWEI
693
FTLGGSPYPG
703
VPVEELFKLL
713
KEGHRMDKPS
723
NCTNELYMMM
733

RDCWHAVPSQ
743
RPTFKQLVED
753
LDRIVALTSN
763
QE
Residue
Distance (Å)
LEU484
3.655
GLY485
3.646
PHE489
3.809
VAL492
4.174
ALA512
3.456
LYS514
3.389
LEU528
4.698
GLU531
3.453
MET535
3.239
ILE545
3.799
VAL559
3.698
VAL561
3.565
GLU562
2.799
Residue
Distance (Å)
TYR563
3.675
ALA564
2.987
SER565
3.487
LYS566
3.846
GLY567
3.411
ASN568
4.588
GLU571
3.302
LEU630
3.662
ILE639
4.914
ALA640
3.606
ASP641
2.887
PHE642
3.748
GLY643
4.584
References  Top
REF 1 Illuminating the molecular mechanisms of tyrosine kinase inhibitor resistance for the FGFR1 gatekeeper mutation: the Achilles' heel of targeted therapy.ACS Chem Biol.2015 May 15;10(5):1319-29.
REF 2 The 1.65?? resolution structure of the complex of AZD4547 with the kinase domain of FGFR1 displays exquisite molecular recognition. Acta Crystallogr D Biol Crystallogr. 2015 Mar;71(Pt 3):525-33.

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