Binding Site Information of Target

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Target General Information
Drug Binding Sites of Target
References
Target General Information  Top
Target ID T23673 Target Info
Target Name Proto-oncogene c-RAF (c-RAF)
Synonyms cRaf; Raf-1; RAF proto-oncogene serine/threonine-protein kinase; RAF
Target Type Clinical trial Target
Gene Name RAF1
Biochemical Class Kinase
UniProt ID
RAF1_HUMAN
Drug Binding Sites of Target  Top
Ligand Name: L-serine-O-phosphate Ligand Info
Structure Description Crystal Structure of human 14-3-3 sigma in Complex with Raf1 peptide (6mer) and stabilisator Fusicoccin PDB:3IQV
Method X-ray diffraction Resolution 1.20 Å Mutation No [1]
PDB Sequence
QRSTT
Residue
Distance (Å)
ARG256
4.334
SER257
4.007
Residue
Distance (Å)
THR258
1.343
THR260
1.316
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Ligand Name: (1E)-5-(1-piperidin-4-yl-3-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydro-1H-inden-1-one oxime Ligand Info
Structure Description Crystal structure of c-raf (raf-1) PDB:3OMV
Method X-ray diffraction Resolution 4.00 Å Mutation No [2]
PDB Sequence
YYWEIEASEV
349
MLSTRIGSGS
359
FGTVYKGKWH
369
GDVAVKILKV
379
VDPTPEQFQA
389

FRNEVAVLRK
399
TRHVNILLFM
409
GYMTKDNLAI
419
VTQWCEGSSL
429
YKHLHVQETK
439

FQMFQLIDIA
449
RQTAQGMDYL
459
HAKNIIHRDM
469
KSNNIFLHEG
479
LTVKIGDFGL
489

ATVPTGSVLW
511
MAPEVIRMQD
521
NNPFSFQSDV
531
YSYGIVLYEL
541
MTGELPYSHI
551

NNRDQIIFMV
561
GRGYASPDLS
571
KLYKNCPKAM
581
KRLVADCVKK
591
VKEERPLFPQ
601

ILSSIELLQH
611
SLPK
Residue
Distance (Å)
ILE355
3.215
GLY356
4.955
SER357
4.543
SER359
4.541
VAL363
3.097
ALA373
3.648
VAL374
4.439
LYS375
2.996
GLU393
3.696
LEU397
4.938
LEU406
4.380
Residue
Distance (Å)
ILE419
4.185
THR421
3.449
GLN422
4.391
TRP423
2.935
CYS424
3.809
SER428
4.610
LYS431
3.008
ASN472
3.319
PHE475
3.044
ASP486
2.511
Ligand Name: Cystein-S-Yl Cacodylate Ligand Info
Structure Description Crystal Structure of KRAS-G13D (GMPPNP-bound) in complex with RAS-binding domain (RBD) and cysteine-rich domain (CRD) of RAF1/CRAF PDB:6XGV
Method X-ray diffraction Resolution 2.11 Å Mutation Yes [3]
PDB Sequence
SNTIRVFLPN
64
KQRTVVNVRN
74
GMSLHDCLMK
84
ALKVRGLQPE
94
CAVFRLLHEH
105

KGKKARLDWN
115
TDAASLIGEE
125
LQVDFLDHVP
135
LTTHNFARKT
145
FLKLAFCDIC
155

QKFLLNGFRC
165
QTCGYKFHEH
175
CSTKVPTMCV
185
DWS
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set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .CAF or .CAF2 or .CAF3 or :3CAF;style chemicals stick;color identity;select .B:92 or .B:93 or .B:94 or .B:96 or .B:97 or .B:129 or .B:130 or .B:131 or .B:134 or .B:135 or .B:136; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
GLN92
2.934
PRO93
3.036
GLU94
1.324
CYS96
1.328
ALA97
4.642
ASP129
4.380
Residue
Distance (Å)
PHE130
3.529
LEU131
2.888
VAL134
3.604
PRO135
3.708
LEU136
3.643
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Ligand Name: [(2S)-2-azaniumyl-2-carboxyethyl] [(2R)-2,3-bis[[(Z)-octadec-9-enoyl]oxy]propyl] phosphate Ligand Info
Structure Description NMR data-driven model of KRas-GMPPNP:RBD-CRD complex tethered to a nanodisc (state A) PDB:6PTS
Method Solution NMR Resolution N.A. Mutation No [4]
PDB Sequence
NTIRVFLPNK
365
QRTVVNVRNG
375
MSLHDCLMKA
385
LKVRGLQPEC
395
CAVFRLLQEH
405

KGKKARLDWN
415
TDAASLIGEE
425
LQVDFLDHVP
435
LTTHNFARKT
445
FLKLAFCDIC
455

QKFLLNGFRC
465
QTCGYKFHEH
475
CSTKVPTMCV
485
DW
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set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .17F or .17F2 or .17F3 or :317F;style chemicals stick;color identity;select .D:475 or .D:456 or .D:457; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
HIS475
4.367
GLN456
3.086
Residue
Distance (Å)
LYS457
2.831
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Ligand Name: Cotylenin A Ligand Info
Structure Description Human 14-3-3 isoform zeta in complex with a diphoyphorylated C-RAF peptide and Cotylenin A PDB:4IHL
Method X-ray diffraction Resolution 2.20 Å Mutation No [5]
PDB Sequence
HRYTPHAQRS
257
TTPNV
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set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .1F5 or .1F52 or .1F53 or :31F5;style chemicals stick;color identity;select .P:260 or .P:261 or .P:262 or .P:263; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
THR260
3.343
PRO261
3.554
Residue
Distance (Å)
ASN262
4.255
VAL263
3.469
Ligand Name: 6,6-Dihydroxy-1-Methoxyhexan-2-One Ligand Info
Structure Description Structure of 14-3-3 isoform sigma in complex with a C-Raf1 peptide and a stabilizing small molecule fragment PDB:3O8I
Method X-ray diffraction Resolution 2.00 Å Mutation No [1]
PDB Sequence
RSTTPNV
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set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .M1T or .M1T2 or .M1T3 or :3M1T;style chemicals stick;color identity;select .B:260 or .B:261 or .B:263; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
THR260
3.944
PRO261
3.634
Residue
Distance (Å)
VAL263
3.166
Ligand Name: Fusicoccin Ligand Info
Structure Description Crystal Structure of human 14-3-3 sigma in Complex with Raf1 peptide (6mer) and stabilisator Fusicoccin PDB:3IQV
Method X-ray diffraction Resolution 1.20 Å Mutation No [1]
PDB Sequence
QRSTT
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set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .FSC or .FSC2 or .FSC3 or :3FSC;style chemicals stick;color identity;select .P:260; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
THR260
3.591
Residue
Distance (Å)
References  Top
REF 1 Impaired binding of 14-3-3 to C-RAF in Noonan syndrome suggests new approaches in diseases with increased Ras signaling. Mol Cell Biol. 2010 Oct;30(19):4698-711.
REF 2 RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature. 2010 Mar 18;464(7287):431-5.
REF 3 KRAS interaction with RAF1 RAS-binding domain and cysteine-rich domain provides insights into RAS-mediated RAF activation. Nat Commun. 2021 Feb 19;12(1):1176.
REF 4 Multivalent assembly of KRAS with the RAS-binding and cysteine-rich domains of CRAF on the membrane. Proc Natl Acad Sci U S A. 2020 Jun 2;117(22):12101-12108.
REF 5 Stabilization of physical RAF/14-3-3 interaction by cotylenin A as treatment strategy for RAS mutant cancers. ACS Chem Biol. 2013 Sep 20;8(9):1869-75.

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