Binding Site Information of Target

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Target General Information
Drug Binding Sites of Target
References
Target General Information  Top
Target ID T30420 Target Info
Target Name SET domain containing 8 (KMT5A)
Synonyms SETD8; SET8; SET07; SET domain-containing protein 8; PRSET7; PR/SET07; PR/SET domain-containing protein 07; PR-Set7; N-lysine methyltransferase KMT5A; Lysine-specific methylase 5A; Lysine N-methyltransferase 5A; Histone-lysine N-methyltransferase KMT5A; H4-K20-HMTase KMT5A
Target Type Preclinical Target
Gene Name KMT5A
Biochemical Class Methyltransferase
UniProt ID
KMT5A_HUMAN
Drug Binding Sites of Target  Top
Ligand Name: Ademetionine Ligand Info
Structure Description Crystal structure of hSETD8 in complex with histone H4K20 norleucine mutant peptide and S-Adenosylmethionine PDB:5TEG
Method X-ray diffraction Resolution 1.30 Å Mutation Yes [1]
PDB Sequence
KSKAELQSEE
202
RKRIDELIES
212
GKEEGMKIDL
222
IDGKGRGVIA
232
TKQFSRGDFV
242

VEYHGDLIEI
252
TDAKKREALY
262
AQDPSTGCYM
272
YYFQYLSKTY
282
CVDATRETNR
292

LGRLINHSKS
302
GNCQTKLHDI
312
DGVPHLILIA
322
SRDIAAGEEL
332
LYDYGDRSKA
342

SIEAHPWLKH
352
Residue
Distance (Å)
GLY225
3.416
LYS226
2.727
GLY227
3.916
ARG228
2.772
TYR245
4.623
CYS270
3.654
TYR271
2.582
ARG295
3.234
Residue
Distance (Å)
LEU296
3.413
ILE297
3.627
ASN298
2.865
HIS299
2.928
TYR336
3.347
HIS347
4.766
TRP349
3.334
Click to View More Binding Site Information of This Target and Ligand Pair
Ligand Name: Norleucine Ligand Info
Structure Description Crystal structure of hSETD8 in complex with histone H4K20 norleucine mutant peptide and S-Adenosylmethionine PDB:5TEG
Method X-ray diffraction Resolution 1.30 Å Mutation Yes [1]
PDB Sequence
KSKAELQSEE
202
RKRIDELIES
212
GKEEGMKIDL
222
IDGKGRGVIA
232
TKQFSRGDFV
242

VEYHGDLIEI
252
TDAKKREALY
262
AQDPSTGCYM
272
YYFQYLSKTY
282
CVDATRETNR
292

LGRLINHSKS
302
GNCQTKLHDI
312
DGVPHLILIA
322
SRDIAAGEEL
332
LYDYGDRSKA
342

SIEAHPWLKH
352
Residue
Distance (Å)
TYR245
3.795
CYS270
3.917
TYR271
4.447
MET272
3.115
Residue
Distance (Å)
TYR273
3.467
TYR274
2.848
TYR334
3.464
TYR336
3.323
Ligand Name: S-Ethyl-L-cysteine Ligand Info
Structure Description Cryo-EM structure of the histone methyltransferase SET8 bound to H4K20Ecx-nucleosome PDB:7XPX
Method Electron microscopy Resolution 3.20 Å Mutation Yes [2]
PDB Sequence
PVRRSSRKSK
195
AELQSEERKR
205
IDELIESGKE
215
EGMKIDLIDG
225
KGRGVIATKQ
235

FSRGDFVVEY
245
HGDLIEITDA
255
KKREALYAQD
265
PSTGCYMYYF
275
QYLSKTYCVD
285

ATRETNRLGR
295
LINHSKCGNC
305
QTKLHDIDGV
315
PHLILIASRD
325
IAAGEELLYD
335

YGDRSKASIE
345
AHPWLKH
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .ECX or .ECX2 or .ECX3 or :3ECX;style chemicals stick;color identity;select .K:245 or .K:270 or .K:271 or .K:272 or .K:273 or .K:274 or .K:334 or .K:336 or .K:337 or .K:338; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
TYR245
4.399
CYS270
4.366
TYR271
4.643
MET272
3.261
TYR273
3.293
Residue
Distance (Å)
TYR274
2.475
TYR334
4.298
TYR336
3.454
GLY337
4.584
ASP338
3.564
Ligand Name: N-[3-[[7-(2-aminoethoxy)-6-methoxy-2-pyrrolidin-1-ylquinazolin-4-yl]amino]propyl]prop-2-enamide Ligand Info
Structure Description Structure of human SETD8 in complex with covalent inhibitor MS4138 PDB:6BOZ
Method X-ray diffraction Resolution 2.40 Å Mutation Yes [3]
PDB Sequence
RIDELIESGK
255
EEGMKIDLID
265
GKGRGVIATK
275
QFSRGDFVVE
285
YHGDLIEITD
295

AKKREALYAQ
305
DPSTGCYMYY
315
FQYLSKTYCV
325
DATRETNRLG
335
RLINHSKSGN
345

CQTKLHDIDG
355
VPHLILIASR
365
DIAAGEELLY
375
DYGDRSKAS
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .E1J or .E1J2 or .E1J3 or :3E1J;style chemicals stick;color identity;select .A:286 or .A:309 or .A:310 or .A:311 or .A:312 or .A:313 or .A:314 or .A:335 or .A:336 or .A:337 or .A:338 or .A:339 or .A:348 or .A:359 or .A:361 or .A:375 or .A:377; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
TYR286
3.301
THR309
4.045
GLY310
3.675
CYS311
2.651
TYR312
3.326
MET313
3.599
TYR314
3.748
GLY335
4.748
ARG336
3.241
Residue
Distance (Å)
LEU337
3.895
ILE338
3.556
ASN339
2.895
THR348
3.549
LEU359
3.570
LEU361
3.848
TYR375
3.293
TYR377
3.785
Ligand Name: 2-(4-Methylpiperazin-1-yl)-3-phenylsulfanylnaphthalene-1,4-dione Ligand Info
Structure Description SETD8 in complex with a covalent inhibitor PDB:5W1Y
Method X-ray diffraction Resolution 1.70 Å Mutation Yes [4]
PDB Sequence
SRKSKAELQS
241
EERKRIDELI
251
ESGKEEGMKI
261
DLIDGKGRGV
271
IATKQFSRGD
281

FVVEYHGDLI
291
EITDAKKREA
301
LYAQDPSTGC
311
YMYYFQYLSK
321
TYCVDATRET
331

NRLGRLINHS
341
KSGNCQTKLH
351
DIDGVPHLIL
361
IASRDIAAGE
371
ELLYDYGDRS
381

KASIEAHPWL
391
KH
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .9SV or .9SV2 or .9SV3 or :39SV;style chemicals stick;color identity;select .A:300 or .A:303 or .A:304 or .A:306 or .A:307 or .A:309 or .A:310 or .A:311 or .A:384 or .A:388 or .A:391; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
GLU300
3.858
TYR303
3.624
ALA304
4.115
ASP306
3.594
PRO307
3.954
THR309
2.965
Residue
Distance (Å)
GLY310
3.404
CYS311
1.753
SER384
4.591
HIS388
4.070
LEU391
3.872
Ligand Name: N-[3-[(6,7-dimethoxy-2-pyrrolidin-1-ylquinazolin-4-yl)amino]propyl]propanamide Ligand Info
Structure Description Complex of SETD8 with MS453 PDB:5TH7
Method X-ray diffraction Resolution 1.95 Å Mutation Yes [5]
PDB Sequence
KAELQSEERK
245
RIDELIESGK
255
EEGMKIDLID
265
GKGRGVIATK
275
QFSRGDFVVE
285

YHGDLIEITD
295
AKKREALYAQ
305
DPSTGCYMYY
315
FQYLSKTYCV
325
DATRETNRLG
335

RLINHSKSGN
345
CQTKLHDIDG
355
VPHLILIASR
365
DIAAGEELLY
375
DYG
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .7BY or .7BY2 or .7BY3 or :37BY;style chemicals stick;color identity;select .A:286 or .A:309 or .A:310 or .A:311 or .A:312 or .A:313 or .A:314 or .A:335 or .A:336 or .A:337 or .A:338 or .A:339 or .A:348 or .A:359 or .A:361 or .A:375 or .A:377; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
TYR286
3.286
THR309
4.302
GLY310
3.925
CYS311
2.755
TYR312
3.442
MET313
3.520
TYR314
3.668
GLY335
4.993
ARG336
3.348
Residue
Distance (Å)
LEU337
4.055
ILE338
3.387
ASN339
3.876
THR348
3.448
LEU359
3.745
LEU361
4.001
TYR375
3.229
TYR377
3.752
Ligand Name: 7-(2-Aminoethoxy)-6-Methoxy-2-(Pyrrolidin-1-Yl)-N-[5-(Pyrrolidin-1-Yl)pentyl]quinazolin-4-Amine Ligand Info
Structure Description human SETD8 in complex with MS2177 PDB:5T5G
Method X-ray diffraction Resolution 2.10 Å Mutation Yes [5]
PDB Sequence
SKAELQSEER
244
KRIDELIESG
254
KEEGMKIDLI
264
DGKGRGVIAT
274
KQFSRGDFVV
284

EYHGDLIEIT
294
DAKKREALYA
304
QDPSTGCYMY
314
YFQYLSKTYC
324
VDATRETNRL
334

GRLINHSKSG
344
NCQTKLHDID
354
GVPHLILIAS
364
RDIAAGEELL
374
YDY
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .75P or .75P2 or .75P3 or :375P;style chemicals stick;color identity;select .A:269 or .A:286 or .A:310 or .A:311 or .A:312 or .A:313 or .A:314 or .A:335 or .A:336 or .A:337 or .A:338 or .A:339 or .A:348 or .A:359 or .A:361 or .A:375 or .A:377; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
ARG269
4.768
TYR286
3.273
GLY310
4.218
CYS311
2.798
TYR312
3.348
MET313
3.429
TYR314
3.743
GLY335
4.834
ARG336
3.498
Residue
Distance (Å)
LEU337
3.565
ILE338
3.533
ASN339
2.669
THR348
3.745
LEU359
3.423
LEU361
3.790
TYR375
3.343
TYR377
3.468
References  Top
REF 1 Turning a Substrate Peptide into a Potent Inhibitor for the Histone Methyltransferase SETD8. ACS Med Chem Lett. 2016 Oct 11;7(12):1102-1106.
REF 2 Structural basis of nucleosomal H4K20 methylation by methyltransferase SET8. FASEB J. 2022 Jun;36(6):e22338.
REF 3 The dynamic conformational landscape of the protein methyltransferase SETD8. Elife. 2019 May 13;8:e45403.
REF 4 SETD8 in complex with a covalent inhibitor
REF 5 Structure-Based Design of a Covalent Inhibitor of the SET Domain-Containing Protein 8 (SETD8) Lysine Methyltransferase. J Med Chem. 2016 Nov 10;59(21):9881-9889.

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