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 T40556 Target Info
Target Name Bromodomain-containing protein 4 (BRD4)
Synonyms Protein HUNK1; HUNK1
Target Type Clinical trial Target
Gene Name BRD4
Biochemical Class Bromodomain
UniProt ID
BRD4_HUMAN
Ligand General Information  Top
Ligand Name MS417 Ligand Info
Canonical SMILES CC1=C(SC2=C1C(=NC(C3=NN=C(N32)C)CC(=O)OC)C4=CC=C(C=C4)Cl)C
InChI 1S/C20H19ClN4O2S/c1-10-11(2)28-20-17(10)18(13-5-7-14(21)8-6-13)22-15(9-16(26)27-4)19-24-23-12(3)25(19)20/h5-8,15H,9H2,1-4H3/t15-/m0/s1
InChIKey GGRCIHACOIMRKY-HNNXBMFYSA-N
PubChem Compound ID 59190723
Drug Binding Sites of Target  Top
PDB ID: 4F3I      Crystal structure of the first bromodomain of human BRD4 in complex with MS417 inhibitor
Method X-ray diffraction Resolution 1.40 Å Mutation No [1]
PDB Sequence
SMNPPPPETS
51
NPNKPKRQTN
61
QLQYLLRVVL
71
KTLWKHQFAW
81
PFQQPVDAVK
91

LNLPDYYKII
101
KTPMDMGTIK
111
KRLENNYYWN
121
AQECIQDFNT
131
MFTNCYIYNK
141

PGDDIVLMAE
151
ALEKLFLQKI
161
NELPTEE
Residue
Distance (Å)
TRP81
3.572
PRO82
3.414
PHE83
3.709
GLN85
4.513
VAL87
3.852
LEU92
3.618
LEU94
3.651
Residue
Distance (Å)
TYR97
4.359
CYS136
4.253
TYR139
3.851
ASN140
3.093
ASP145
3.618
ILE146
3.515
MET149
3.557
PDB ID: 6DUV      Crystal structure of the second bromodomain of human BRD4 in complex with MS417 inhibitor
Method X-ray diffraction Resolution 1.80 Å Mutation No [2]
PDB Sequence
KVSEQLKCCS
358
GILKEMFAKK
368
HAAYAWPFYK
378
PVDVEALGLH
388
DYCDIIKHPM
398

DMSTIKSKLE
408
AREYRDAQEF
418
GADVRLMFSN
428
CYKYNPPDHE
438
VVAMARKLQD
448

VFEMRFAKMP
458
Residue
Distance (Å)
TRP374
3.677
PRO375
3.348
PHE376
3.655
VAL380
3.777
LEU385
3.481
GLY386
4.153
LEU387
3.599
TYR390
4.774
Residue
Distance (Å)
CYS429
3.918
TYR432
3.252
ASN433
2.997
PRO434
3.420
HIS437
3.148
GLU438
3.434
VAL439
3.557
MET442
3.823
PDB ID: 5UEU      BRD4_BD2_A-1107604
Method X-ray diffraction Resolution 2.26 Å Mutation No [3]
PDB Sequence
SHMEQLKCCS
358
GILKEMFAKK
368
HAAYAWPFYK
378
PVDVEALGLH
388
DYCDIIKHPM
398

DMSTIKSKLE
408
AREYRDAQEF
418
GADVRLMFSN
428
CYKYNPPDHE
438
VVAMARKLQD
448

VFEMRFAKM
Residue
Distance (Å)
TRP374
2.763
PRO375
2.878
PHE376
2.989
LYS378
5.000
VAL380
3.018
LEU385
3.131
LEU387
2.919
TYR390
4.602
Residue
Distance (Å)
MET425
4.940
CYS429
3.920
TYR432
3.288
ASN433
2.479
GLU438
3.629
VAL439
3.366
MET442
3.014
References  Top
REF 1 Down-regulation of NF- B transcriptional activity in HIV-associated kidney disease by BRD4 inhibition. J Biol Chem. 2012 Aug 17;287(34):28840-51.
REF 2 Role of Bound Water Molecules in Differential Recognition of Di-Acetylated Histone Peptides by the BRD4 Bromodomains
REF 3 Fragment-Based, Structure-Enabled Discovery of Novel Pyridones and Pyridone Macrocycles as Potent Bromodomain and Extra-Terminal Domain (BET) Family Bromodomain Inhibitors. J Med Chem. 2017 May 11;60(9):3828-3850.

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