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 T87686 Target Info
Target Name Histone-lysine N-methyltransferase (HLNM)
Synonyms Lysine N-methyltransferase 4; KMT4; KIAA1814; Histone-lysine N-methyltransferase, H3 lysine-79 specific; Histone H3-K79 methyltransferase; H3-K79-HMTase; DOT1-like protein
Target Type Clinical trial Target
Gene Name DOT1L
Biochemical Class Methyltransferase
UniProt ID
DOT1L_HUMAN
Ligand General Information  Top
Ligand Name EPZ-004777 Ligand Info
Canonical SMILES CC(C)N(CCCNC(=O)NC1=CC=C(C=C1)C(C)(C)C)CC2C(C(C(O2)N3C=CC4=C(N=CN=C43)N)O)O
InChI 1S/C28H41N7O4/c1-17(2)34(13-6-12-30-27(38)33-19-9-7-18(8-10-19)28(3,4)5)15-21-22(36)23(37)26(39-21)35-14-11-20-24(29)31-16-32-25(20)35/h7-11,14,16-17,21-23,26,36-37H,6,12-13,15H2,1-5H3,(H2,29,31,32)(H2,30,33,38)/t21-,22-,23-,26-/m1/s1
InChIKey WXRGFPHDRFQODR-ICLZECGLSA-N
PubChem Compound ID 56962336
Drug Binding Sites of Target  Top
PDB ID: 4EKI      Crystal Structure of DOT1L in complex with EPZ004777
Method X-ray diffraction Resolution 2.85 Å Mutation No [1]
PDB Sequence
KLELRLKSPV
13
GAEPAVYPWP
23
LPVYDKHHDA
33
AHEIIETIRW
43
VCEEIPDLKL
53

AMENYDYDTK
66
SFESMQRLCD
76
KYNRAIDSIH
86
QLWKGTTQPM
96
KLNTRPSTGL
106

LRHILQQVYN
116
HSVTDPEKLN
126
SPEVYGETSF
141
DLVAQMIDEI
151
KMTDDDLFVD
161

LGSGVGQVVL
171
QVAAATNCKH
181
HYGVEKADIP
191
AKYAETMDRE
201
FRKWMKWYGK
211

KHAEYTLERG
221
DFLSEEWRER
231
IANTSVIFVN
241
NFAFGPEVDH
251
QLKERFANMK
261

EGGRIVSSKP
271
FAPLNFRINS
281
RNLSDIGTIM
291
RVVELSPLKG
301
SVSWTGKPVS
311

YYLHTIDRTI
321
LENYFSSLK
Residue
Distance (Å)
VAL135
3.832
TYR136
3.433
SER140
4.643
LEU143
3.785
VAL144
4.381
MET147
4.090
ASP161
2.803
LEU162
3.811
GLY163
2.814
SER164
3.336
GLY165
3.847
GLN168
4.281
VAL169
3.548
VAL185
3.793
GLU186
2.532
Residue
Distance (Å)
LYS187
3.104
ALA188
3.600
PRO191
3.911
GLY221
3.124
ASP222
3.206
PHE223
3.067
LEU224
4.319
PHE239
3.788
VAL240
3.774
ASN241
3.427
PHE245
3.839
VAL267
3.788
SER268
4.072
SER269
4.041
TYR312
3.857
PDB ID: 4ER5      Crystal structure of human DOT1L in complex with 2 molecules of EPZ004777
Method X-ray diffraction Resolution 2.57 Å Mutation No [2]
PDB Sequence
KLELRLKSPV
13
GAEPAVYPWP
23
LPVYDKHHDA
33
AHEIIETIRW
43
VCEEIPDLKL
53

AMEYDTKSFE
69
SMQRLCDKYN
79
RAIDSIHQLW
89
KGTTQPMKLN
99
TRPSTGLLRH
109

ILQQVYNHSV
119
TDPEKLNNYE
129
PFSPEVYGET
139
SFDLVAQMID
149
EIKMTDDDLF
159

VDLGSGVGQV
169
VLQVAAATNC
179
KHHYGVEKAD
189
IPAKYAETMD
199
REFRKWMKWY
209

GKKHAEYTLE
219
RGDFLSEEWR
229
ERIANTSVIF
239
VNNFAFGPEV
249
DHQLKERFAN
259

MKEGGRIVSS
269
KPFAPLNFRI
279
NSRNLSDIGT
289
IMRVVELSPL
299
KGSVSKPVSY
312

YLHTIDRTIL
322
ENYFSSLKNP
332
KLREEQEAA
Residue
Distance (Å)
ARG108
4.729
LEU111
3.415
GLN112
3.841
TYR115
3.265
PRO122
3.149
GLU123
3.374
LEU125
2.460
ASN126
3.277
ASN127
3.348
TYR128
3.480
GLU129
4.759
PHE131
4.460
PRO133
3.370
GLU134
4.700
TYR136
3.098
GLY137
3.416
SER140
3.847
PHE141
3.851
LEU143
3.629
VAL144
4.153
MET147
4.054
ASP161
3.015
LEU162
4.142
GLY163
2.833
Residue
Distance (Å)
SER164
3.553
GLY165
3.442
VAL166
4.889
GLN168
2.933
VAL169
3.471
VAL185
3.701
GLU186
2.235
LYS187
3.156
ALA188
3.966
PRO191
3.886
MET198
4.903
GLY221
3.496
ASP222
2.995
PHE223
3.232
LEU224
4.514
PHE239
3.807
VAL240
3.750
ASN241
3.550
PHE245
3.696
VAL267
3.995
SER268
3.456
SER269
3.656
TYR312
4.421
PDB ID: 4ER3      Crystal Structure of Human DOT1L in complex with inhibitor EPZ004777
Method X-ray diffraction Resolution 2.40 Å Mutation No [2]
PDB Sequence
KLELRLKSPV
13
GAEPAVYPWP
23
LPVYDKHHDA
33
AHEIIETIRW
43
VCEEIPDLKL
53

AMENYVLIDY
63
DTKSFESMQR
73
LCDKYNRAID
83
SIHQLWKGTT
93
QPMKLNTRPS
103

TGLLRHILQQ
113
VYNHSVTDPE
123
KLNNETSFDL
143
VAQMIDEIKM
153
TDDDLFVDLG
163

SGVGQVVLQV
173
AAATNCKHHY
183
GVEKADIPAK
193
YAETMDREFR
203
KWMKWYGKKH
213

AEYTLERGDF
223
LSEEWRERIA
233
NTSVIFVNNF
243
AFGPEVDHQL
253
KERFANMKEG
263

GRIVSSKPFA
273
PLNFRINSRN
283
LSDIGTIMRV
293
VELSPLKGSV
310
SYYLHTIDRT
320

ILENYFSSLK
330
N
Residue
Distance (Å)
LEU143
3.950
VAL144
4.404
MET147
3.499
ASP161
3.047
LEU162
3.998
GLY163
2.775
SER164
3.533
GLY165
3.708
GLN168
4.144
VAL169
3.600
VAL185
3.788
GLU186
2.367
LYS187
3.274
ALA188
3.949
Residue
Distance (Å)
PRO191
4.003
GLY221
3.433
ASP222
3.304
PHE223
3.162
LEU224
4.079
PHE239
4.010
VAL240
3.759
ASN241
3.457
PHE243
4.493
PHE245
3.505
VAL267
3.772
SER268
3.622
SER269
4.023
TYR312
3.629
References  Top
REF 1 Conformational adaptation drives potent, selective and durable inhibition of the human protein methyltransferase DOT1L. Chem Biol Drug Des. 2012 Dec;80(6):971-80.
REF 2 Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors. Nat Commun. 2012;3:1288.

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