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 T99089 Target Info
Target Name Serine/threonine-protein kinase B-raf (BRAF)
Synonyms V-Raf murine sarcoma viral oncogene homolog B1; RAFB1; Proto-oncogene B-Raf; P94; BRAF1; BRAF(V599E); BRAF serine/threonine kinase; B-raf protein; B-Raf
Target Type Successful Target
Gene Name BRAF
Biochemical Class Kinase
UniProt ID
BRAF_HUMAN
Ligand General Information  Top
Ligand Name Dabrafenib Ligand Info
Canonical SMILES CC(C)(C)C1=NC(=C(S1)C2=NC(=NC=C2)N)C3=C(C(=CC=C3)NS(=O)(=O)C4=C(C=CC=C4F)F)F
InChI 1S/C23H20F3N5O2S2/c1-23(2,3)21-30-18(19(34-21)16-10-11-28-22(27)29-16)12-6-4-9-15(17(12)26)31-35(32,33)20-13(24)7-5-8-14(20)25/h4-11,31H,1-3H3,(H2,27,28,29)
InChIKey BFSMGDJOXZAERB-UHFFFAOYSA-N
PubChem Compound ID 44462760
Drug Binding Sites of Target  Top
PDB ID: 5HIE      BRAF Kinase domain b3aC loop deletion mutant in complex with dabrafenib
Method X-ray diffraction Resolution 3.00 Å Mutation No [1]
PDB Sequence
DWEIPDGQIT
458
VGQRIGSGSF
468
GTVYKGKWHG
478
DVAVKMLTPQ
493
QLQAFKNEVG
503

VLRKTRHVNI
513
LLFMGYSTKP
523
QLAIVTQWCE
533
GSSLYHHLHI
543
IETKFEMIKL
553

IDIARQTAQG
563
MDYLHAKSII
573
HRDLKSNNIF
583
LHEDLTVKIG
593
DFGLATVKSR
603

GSILWMAPEV
624
IRMQDKNPYS
634
FQSDVYAFGI
644
VLYELMTGQL
654
PYSNINNRDQ
664

IIFMVGRGYL
674
SPDLSKVRSN
684
CPKAMKRLMA
694
ECLKKKRDER
704
PLFPQILASI
714

ELLARSLP
Residue
Distance (Å)
ILE463
3.961
GLY464
3.589
SER465
3.815
GLY466
3.597
PHE468
3.451
VAL471
3.378
ALA481
3.656
LYS483
3.200
PHE498
3.716
VAL504
4.181
LEU505
3.418
THR508
4.993
ILE513
4.849
LEU514
3.118
Residue
Distance (Å)
LEU515
4.574
PHE516
3.754
ILE527
3.342
THR529
3.701
GLN530
3.153
TRP531
3.445
CYS532
2.842
ASN580
4.174
PHE583
3.608
ILE592
3.964
GLY593
3.238
ASP594
2.908
PHE595
2.897
PDB ID: 4XV2      B-Raf Kinase V600E oncogenic mutant in complex with Dabrafenib
Method X-ray diffraction Resolution 2.50 Å Mutation Yes [2]
PDB Sequence
DWEIPDGQIT
458
VGQRIGSGSF
468
GTVYKGKWHG
478
DVAVKMLNVP
490
TPQQLQAFKN
500

EVGVLRKTRH
510
VNILLFMGYS
520
TKPQLAIVTQ
530
WCEGSSLYHH
540
LHASETKFEM
550

KKLIDIARQT
560
ARGMDYLHAK
570
SIIHRDLKSN
580
NIFLHEDNTV
590
KIGDFGGSIL
618

WMAPEVIRPY
633
SFQSDVYAFG
643
IVLYELMTGQ
653
LPYSNINNRD
663
QIIEMVGRGS
673

LSPDLSKVRS
683
NCPKRMKRLM
693
AECLKKKRDE
703
RPSFPRILAE
713
IEELARE
Residue
Distance (Å)
ILE463
4.245
GLY464
3.646
SER465
3.673
GLY466
3.826
PHE468
3.667
VAL471
3.304
ALA481
3.614
LYS483
2.878
LEU505
3.291
THR508
4.773
ILE513
4.611
LEU514
3.116
LEU515
4.412
Residue
Distance (Å)
PHE516
3.768
ILE527
3.103
THR529
3.502
GLN530
3.311
TRP531
3.431
CYS532
2.911
ASN580
4.987
PHE583
3.676
ILE592
4.005
GLY593
3.110
ASP594
2.822
PHE595
2.873
PDB ID: 6V2U      Crystal structure of the insect cell-expressed WT-BRAF kinase in complex with Dabrafenib
Method X-ray diffraction Resolution 3.78 Å Mutation No [3]
PDB Sequence
DWEIPDGQIT
458
VGQRIGSGSF
468
GTVYKGKWHG
478
DVAVKMLNVT
488
APTPQQLQAF
498

KNEVGVLRKT
508
RHVNILLFMG
518
YSTKPQLAIV
528
TQWCEGSSLY
538
HHLHIIETKF
548

EMIKLIDIAR
558
QTAQGMDYLH
568
AKSIIHRDLK
578
SNNIFLHEDL
588
TVKIGDFSGS
616

ILWMAPEVIR
626
MQDKNPYSFQ
636
SDVYAFGIVL
646
YELMTGQLPY
656
SNINNRDQII
666

FMVGRGYLSP
676
DLSKVRSNCP
686
KAMKRLMAEC
696
LKKKRDERPL
706
FPQILASIEL
716

LARSL
Residue
Distance (Å)
ILE463
4.353
GLY464
4.123
SER465
3.745
GLY466
3.970
PHE468
4.397
VAL471
3.378
ALA481
4.016
LYS483
2.328
LEU505
3.252
THR508
4.599
ILE513
4.638
LEU514
3.193
LEU515
4.392
Residue
Distance (Å)
PHE516
3.528
ILE527
3.311
THR529
3.412
GLN530
3.620
TRP531
3.570
CYS532
2.949
ASN580
4.460
ASN581
4.583
PHE583
3.630
ILE592
4.015
GLY593
3.293
ASP594
2.848
PHE595
3.030
PDB ID: 5CSW      B-RAF in complex with Dabrafenib
Method X-ray diffraction Resolution 2.66 Å Mutation Yes [4]
PDB Sequence
DWEIPDGQIT
458
VGQRIGSGSF
468
GTVYKGKWHG
478
DVAVKMLNVT
488
APTPQQLQAF
498

KNEVGVLRKT
508
RHVNILLFMG
518
YSTKPQLAIV
528
TQWCEGSSLY
538
HHLHASETKF
548

EMKKLIDIAR
558
QTARGMDYLH
568
AKSIIHRDLK
578
SNNIFLHEDN
588
TVKIGDFGSI
617

LWMAPEVIRM
627
QDSNPYSFQS
637
DVYAFGIVLY
647
ELMTGQLPYS
657
NINNRDQIIE
667

MVGRGSLSPD
677
LSKVRSNCPK
687
RMKRLMAECL
697
KKKRDERPSF
707
PRILAEIEEL
717

AREL
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .P06 or .P062 or .P063 or :3P06;style chemicals stick;color identity;select .A:463 or .A:464 or .A:465 or .A:466 or .A:468 or .A:471 or .A:481 or .A:483 or .A:505 or .A:508 or .A:513 or .A:514 or .A:515 or .A:516 or .A:527 or .A:529 or .A:530 or .A:531 or .A:532 or .A:580 or .A:581 or .A:583 or .A:592 or .A:593 or .A:594 or .A:595; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
ILE463
4.339
GLY464
3.783
SER465
3.409
GLY466
3.641
PHE468
3.926
VAL471
3.423
ALA481
3.923
LYS483
2.737
LEU505
3.122
THR508
4.910
ILE513
4.667
LEU514
3.457
LEU515
4.501
Residue
Distance (Å)
PHE516
3.777
ILE527
3.296
THR529
3.545
GLN530
3.473
TRP531
3.479
CYS532
2.870
ASN580
4.984
ASN581
4.728
PHE583
3.574
ILE592
4.214
GLY593
3.159
ASP594
2.963
PHE595
3.040
References  Top
REF 1 Activation Mechanism of Oncogenic Deletion Mutations in BRAF, EGFR, and HER2. Cancer Cell. 2016 Apr 11;29(4):477-493.
REF 2 RAF inhibitors that evade paradoxical MAPK pathway activation. Nature. 2015 Oct 22;526(7574):583-6.
REF 3 Crystal structure of the insect cell-expressed WT-BRAF kinase in complex with Dabrafenib
REF 4 A Novel RAF Kinase Inhibitor with DFG-Out-Binding Mode: High Efficacy in BRAF-Mutant Tumor Xenograft Models in the Absence of Normal Tissue Hyperproliferation. Mol Cancer Ther. 2016 Mar;15(3):354-65.

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