Binding Site Information of Target

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Target General Information
Drug Binding Sites of Target
References
Target General Information  Top
Target ID T36741 Target Info
Target Name p53-binding protein Mdm4 (MDM4)
Synonyms Protein Mdmx; Mdm2-like p53-binding protein; Double minute 4 protein
Target Type Clinical trial Target
Gene Name MDM4
Biochemical Class MDM2/MDM4 family
UniProt ID
MDM4_HUMAN
Drug Binding Sites of Target  Top
Ligand Name: 7-methoxy-~{N}-[(3~{S})-1-(4-methylphenyl)pyrrolidin-3-yl]-1~{H}-indole-3-carboxamide Ligand Info
Structure Description HDMX (14-111; C17S) COMPLEXED WITH COMPOUND 16 AT 1.20A; Structural states of Hdm2 and HdmX: X-ray elucidation of adaptations and binding interactions for different chemical compound classes PDB:6Q9Y
Method X-ray diffraction Resolution 1.20 Å Mutation Yes [1]
PDB Sequence
QVRPKLPLLK
36
ILHAAGAQGE
46
MFTVKEVMHY
56
LGQYIMVKQL
66
YDQQEQHMVY
76

CGGDLLGELL
86
GRQSFSVKDP
96
SPLYDMLRKN
106
LVTLA
Residue
Distance (Å)
MET54
3.838
LEU57
3.851
GLY58
3.463
ILE61
3.496
MET62
3.919
TYR67
3.357
GLN72
2.791
HIS73
4.279
Residue
Distance (Å)
MET74
4.859
VAL75
3.451
PHE91
3.346
VAL93
3.310
PRO96
3.704
LEU99
3.536
TYR100
3.851
LEU103
3.766
Ligand Name: (4~{S})-4-(4-chlorophenyl)-5-[(1~{S})-1-(3-chlorophenyl)ethyl]-2-(2,4-dimethoxypyrimidin-5-yl)-3-propan-2-yl-4~{H}-pyrrolo[3,4-d]imidazol-6-one Ligand Info
Structure Description X-ray structure of compound 15 bound to HdmX: Structural states of Hdm2 and HdmX: X-ray elucidation of adaptations and binding interactions for different chemical compound classes PDB:6Q9W
Method X-ray diffraction Resolution 1.55 Å Mutation Yes [1]
PDB Sequence
NQVRPKLPLL
35
KILHAAGAQG
45
EMFTVKEVMH
55
YLGQYIMVKQ
65
LYDQQEQHMV
75

YCGGDLLGEL
85
LGRQSFSVKD
95
PSPLYDMLRK
105
NLVTLA
Residue
Distance (Å)
MET54
3.540
LEU57
3.707
GLY58
3.497
GLN59
4.826
ILE61
3.450
MET62
3.692
TYR67
3.186
ASP68
4.115
GLN69
3.655
GLN72
3.216
Residue
Distance (Å)
HIS73
3.718
MET74
3.133
VAL75
3.864
PHE91
3.932
SER92
4.621
VAL93
3.791
PRO96
3.478
LEU99
3.534
TYR100
3.089
Ligand Name: 5-[(6-chloro-7-methylindol-3-ylidene)methyl]-3-[(3,4-difluorophenyl)methyl]-4-hydroxy-1H-imidazol-2-one Ligand Info
Structure Description Structure of hDMX with Dimer Inducing Indolyl Hydantoin RO-2443 PDB:3U15
Method X-ray diffraction Resolution 1.80 Å Mutation Yes [2]
PDB Sequence
QVRPKLPLLK
35
ILHAAGAQGE
45
MFTVKEVMHY
55
LGQYIMVKQL
65
YDQQEQHMVY
75

CGGDLLGELL
85
GRQSFSVKDP
95
SPLYDMLRKN
105
LV
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .03M or .03M2 or .03M3 or :303M;style chemicals stick;color identity;select .A:57 or .A:60 or .A:61 or .A:66 or .A:71 or .A:72 or .A:74 or .A:92; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
GLY57
3.623
ILE60
3.144
MET61
3.441
TYR66
2.995
Residue
Distance (Å)
GLN71
2.871
HIS72
4.333
VAL74
4.243
VAL92
3.610
Ligand Name: 6-chloranyl-3-[3-[(1~{S})-1-(4-chlorophenyl)ethyl]-5-phenyl-imidazol-4-yl]-~{N}-[2-(4-cyclohexylpiperazin-1-yl)ethyl]-1~{H}-indole-2-carboxamide Ligand Info
Structure Description HDMX (14-111; C17S) COMPLEXED WITH COMPOUND 13 AT 2.1A; Structural states of Hdm2 and HdmX: X-ray elucidation of adaptations and binding interactions for different chemical compound classes PDB:6Q9Q
Method X-ray diffraction Resolution 2.10 Å Mutation Yes [1]
PDB Sequence
NQVRPKLPLL
35
KILHAAGAQG
45
EMFTVKEVMH
55
YLGQYIMVKQ
65
LYDQQEQHMV
75

YCGGDLLGEL
85
LGRQSFSVKD
95
PSPLYDMLRK
105
NLVT
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .HUE or .HUE2 or .HUE3 or :3HUE;style chemicals stick;color identity;select .A:54 or .A:55 or .A:57 or .A:58 or .A:61 or .A:62 or .A:67 or .A:72 or .A:75 or .A:91 or .A:93 or .A:96 or .A:99 or .A:100; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
MET54
2.890
HIS55
3.955
LEU57
3.793
GLY58
3.269
ILE61
3.664
MET62
3.397
TYR67
3.688
Residue
Distance (Å)
GLN72
3.097
VAL75
4.757
PHE91
4.003
VAL93
3.406
PRO96
3.462
LEU99
3.140
TYR100
3.796
Ligand Name: 3-[[6-chloranyl-3-[3-[(1~{S})-1-(2,4-dichlorophenyl)ethyl]-5-phenyl-imidazol-4-yl]-1~{H}-indol-2-yl]carbonylamino]-4-[4-(2-oxidanylidene-1,3-oxazinan-3-yl)piperidin-1-yl]benzoic acid Ligand Info
Structure Description HDMX (14-111; C17S) COMPLEXED WITH COMPOUND 14 AT 2.4A: Structural states of Hdm2 and HdmX: X-ray elucidation of adaptations and binding interactions for different chemical compound classes PDB:6Q9S
Method X-ray diffraction Resolution 2.40 Å Mutation Yes [1]
PDB Sequence
GQINQVRPKL
32
PLLKILHAAG
42
AQGEMFTVKE
52
VMHYLGQYIM
62
VKQLYDQQEQ
72

HMVYCGGDLL
82
GELLGRQSFS
92
VKDPSPLYDM
102
LRKNLVT
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .HRN or .HRN2 or .HRN3 or :3HRN;style chemicals stick;color identity;select .A:51 or .A:54 or .A:55 or .A:57 or .A:58 or .A:61 or .A:62 or .A:67 or .A:72 or .A:75 or .A:82 or .A:91 or .A:93 or .A:96 or .A:99 or .A:100; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
LYS51
3.658
MET54
2.751
HIS55
2.760
LEU57
3.644
GLY58
3.479
ILE61
3.594
MET62
3.498
TYR67
3.638
Residue
Distance (Å)
GLN72
3.371
VAL75
4.492
LEU82
4.907
PHE91
4.008
VAL93
3.520
PRO96
3.971
LEU99
3.523
TYR100
3.962
Ligand Name: 4-[(4~{S})-5-(5-chloranyl-2-oxidanylidene-1~{H}-pyridin-3-yl)-2-[2-(dimethylamino)-4-methoxy-pyrimidin-5-yl]-6-oxidanylidene-3-propan-2-yl-4~{H}-pyrrolo[3,4-c]pyrazol-4-yl]benzenecarbonitrile Ligand Info
Structure Description HDMX (14-111; C17S) COMPLEXED WITH COMPOUND 12 AT 2.4A; Structural states of Hdm2 and HdmX: X-ray elucidation of adaptations and binding interactions for different chemical compound classes PDB:6Q9U
Method X-ray diffraction Resolution 2.40 Å Mutation Yes [1]
PDB Sequence
INQVRPKLPL
34
LKILHAAGAQ
44
GEMFTVKEVM
54
HYLGQYIMVK
64
QLYDQQEQHM
74

VYCGGDLLGE
84
LLGRQSFSVK
94
DPSPLYDMLR
104
KNLVTL
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .HRE or .HRE2 or .HRE3 or :3HRE;style chemicals stick;color identity;select .A:54 or .A:57 or .A:58 or .A:59 or .A:61 or .A:62 or .A:67 or .A:69 or .A:72 or .A:75 or .A:82 or .A:86 or .A:91 or .A:93 or .A:96 or .A:99 or .A:100; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
MET54
3.314
LEU57
3.835
GLY58
3.439
GLN59
4.962
ILE61
3.297
MET62
3.755
TYR67
3.234
GLN69
4.997
GLN72
3.462
Residue
Distance (Å)
VAL75
3.878
LEU82
4.428
LEU86
4.941
PHE91
3.851
VAL93
3.673
PRO96
2.765
LEU99
3.271
TYR100
3.259
Ligand Name: nutlin-3A Ligand Info
Structure Description Crystal structure of the N-terminal domain of human MdmX protein in complex with Nutlin3a PDB:7C3Y
Method X-ray diffraction Resolution 1.63 Å Mutation No [3]
PDB Sequence
DLENLYFQGS
21
QINQVRPKLP
31
LLKILHAAGA
41
QGEMFTVKEV
51
MHYLGQYIMV
61

KQLYDQQEQH
71
MVYCGGDLLG
81
ELLGRQSFSV
91
KDPSPLYDML
101
RKNLVT
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .NUT or .NUT2 or .NUT3 or :3NUT;style chemicals stick;color identity;select .A:52 or .A:53 or .A:55 or .A:56 or .A:57 or .A:59 or .A:60 or .A:65 or .A:70 or .A:71 or .A:72 or .A:73 or .A:80 or .A:89 or .A:91 or .A:92 or .A:94 or .A:97 or .A:98; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
MET52
2.283
HIS53
4.780
LEU55
2.630
GLY56
2.683
GLN57
4.994
ILE59
2.272
MET60
2.529
TYR65
2.952
GLN70
2.638
HIS71
2.429
Residue
Distance (Å)
MET72
4.619
VAL73
2.480
LEU80
4.357
PHE89
3.105
VAL91
2.033
LYS92
4.061
PRO94
2.479
LEU97
2.762
TYR98
3.277
Click to View More Binding Site Information of This Target and Ligand Pair
Ligand Name: N-[(3S)-1-({6-chloro-3-[1-(4-chlorobenzyl)-4-phenyl-1H-imidazol-5-yl]-1H-indol-2-yl}carbonyl)pyrrolidin-3-yl]-N,N',N'-trimethylpropane-1,3-diamine Ligand Info
Structure Description Structure of human MDMX protein in complex with a small molecule inhibitor PDB:3LBJ
Method X-ray diffraction Resolution 1.50 Å Mutation No [4]
PDB Sequence
NQVRPKLPLL
34
KILHAAGAQG
44
EMFTVKEVMH
54
YLGQYIMVKQ
64
LYDQQEQHMV
74

YCGGDLLGEL
84
LGRQSFSVKD
94
PSPLYDMLRK
104
NLV
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .WW8 or .WW82 or .WW83 or :3WW8;style chemicals stick;color identity;select .E:27 or .E:30 or .E:49 or .E:53 or .E:54 or .E:56 or .E:57 or .E:60 or .E:61 or .E:66 or .E:71 or .E:74 or .E:90 or .E:92 or .E:95 or .E:98 or .E:99 or .E:100 or .E:102 or .E:103 or .E:104 or .E:106 or .E:107; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
VAL27
2.232
LYS30
4.661
VAL49
2.834
MET53
2.841
HIS54
3.289
LEU56
3.728
GLY57
3.457
ILE60
3.530
MET61
3.820
TYR66
3.509
GLN71
3.214
VAL74
4.978
Residue
Distance (Å)
PHE90
4.152
VAL92
3.384
PRO95
3.653
LEU98
3.457
TYR99
3.139
ASP100
3.810
LEU102
4.616
ARG103
2.440
LYS104
4.320
LEU106
3.966
VAL107
4.100
Ligand Name: 4-({(4s,5r)-4-(3-Chlorophenyl)-5-(4-Chlorophenyl)-2-[4-Methoxy-2-(Propan-2-Yloxy)phenyl]-4,5-Dihydro-1h-Imidazol-1-Yl}carbonyl)piperazin-2-One Ligand Info
Structure Description Mdmx-295 PDB:2N14
Method Solution NMR Resolution N.A. Mutation No [5]
PDB Sequence
QINQVRPKLP
32
LLKILHAAGA
42
QGEMFTVKEV
52
MHYLGQYIMV
62
KQLYDQQEQH
72

MVYCGGDLLG
82
ELLGRQSFSV
92
KDPSPLYDML
102
RKNLVTLAT
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .49H or .49H2 or .49H3 or :349H;style chemicals stick;color identity;select .A:53 or .A:54 or .A:56 or .A:57 or .A:58 or .A:60 or .A:61 or .A:66 or .A:70 or .A:71 or .A:72 or .A:74 or .A:90 or .A:91 or .A:92 or .A:95 or .A:98; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
MET53
2.340
HIS54
4.231
LEU56
2.899
GLY57
2.838
GLN58
4.562
ILE60
2.419
MET61
2.464
TYR66
3.243
GLU70
4.090
Residue
Distance (Å)
GLN71
2.426
HIS72
2.609
VAL74
2.993
PHE90
2.923
SER91
4.887
VAL92
2.559
PRO95
3.075
LEU98
2.744
Ligand Name: 4-[(4s,5r)-4-(3-Chlorophenyl)-5-(4-Chlorophenyl)-1-(3-Oxidanylidenepiperazin-1-Yl)carbonyl-4,5-Dihydroimidazol-2-Yl]-3-Propan-2-Yloxy-Benzenecarbonitrile Ligand Info
Structure Description Mdmx-057 PDB:2N0U
Method Solution NMR Resolution N.A. Mutation No [5]
PDB Sequence
QINQVRPKLP
32
LLKILHAAGA
42
QGEMFTVKEV
52
MHYLGQYIMV
62
KQLYDQQEQH
72

MVYCGGDLLG
82
ELLGRQSFSV
92
KDPSPLYDML
102
RKNLVTLAT
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .48M or .48M2 or .48M3 or :348M;style chemicals stick;color identity;select .A:53 or .A:54 or .A:56 or .A:57 or .A:58 or .A:60 or .A:61 or .A:66 or .A:71 or .A:72 or .A:73 or .A:74 or .A:81 or .A:90 or .A:91 or .A:92 or .A:94 or .A:95 or .A:98 or .A:99; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
MET53
2.369
HIS54
3.222
LEU56
2.555
GLY57
2.516
GLN58
4.114
ILE60
2.433
MET61
2.294
TYR66
2.851
GLN71
2.681
HIS72
2.455
Residue
Distance (Å)
MET73
4.740
VAL74
2.753
LEU81
4.575
PHE90
2.796
SER91
3.894
VAL92
2.277
ASP94
4.811
PRO95
2.424
LEU98
3.025
TYR99
3.614
Ligand Name: 4-[(4S,5R)-4-(5-bromo-2-fluorophenyl)-5-(4-chlorophenyl)-2-(4-methoxy-2-propan-2-yloxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazin-2-one Ligand Info
Structure Description Mdmx-SJ212 PDB:2N0W
Method Solution NMR Resolution N.A. Mutation No [5]
PDB Sequence
QINQVRPKLP
32
LLKILHAAGA
42
QGEMFTVKEV
52
MHYLGQYIMV
62
KQLYDQQEQH
72

MVYCGGDLLG
82
ELLGRQSFSV
92
KDPSPLYDML
102
RKNLVTLAT
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .48L or .48L2 or .48L3 or :348L;style chemicals stick;color identity;select .A:50 or .A:53 or .A:54 or .A:56 or .A:57 or .A:58 or .A:60 or .A:61 or .A:66 or .A:71 or .A:72 or .A:73 or .A:74 or .A:90 or .A:92 or .A:95 or .A:98 or .A:99 or .A:111; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
LYS50
4.746
MET53
2.486
HIS54
3.612
LEU56
2.318
GLY57
2.665
GLN58
4.843
ILE60
2.511
MET61
2.355
TYR66
3.511
GLN71
2.514
Residue
Distance (Å)
HIS72
2.518
MET73
4.893
VAL74
2.758
PHE90
3.020
VAL92
2.346
PRO95
3.313
LEU98
2.954
TYR99
3.280
THR111
4.829
Ligand Name: 4-[[(4s,5r)-5-(4-Chlorophenyl)-4-(3-Methoxyphenyl)-2-(4-Methoxy-2-Propan-2-Yloxy-Phenyl)-4,5-Dihydroimidazol-1-Yl]carbonyl]piperazin-2-One Ligand Info
Structure Description Mdmx-298 PDB:2N06
Method Solution NMR Resolution N.A. Mutation No [5]
PDB Sequence
QINQVRPKLP
32
LLKILHAAGA
42
QGEMFTVKEV
52
MHYLGQYIMV
62
KQLYDQQEQH
72

MVYCGGDLLG
82
ELLGRQSFSV
92
KDPSPLYDML
102
RKNLVTLAT
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .44Z or .44Z2 or .44Z3 or :344Z;style chemicals stick;color identity;select .A:49 or .A:52 or .A:53 or .A:56 or .A:57 or .A:60 or .A:61 or .A:66 or .A:71 or .A:72 or .A:73 or .A:74 or .A:81 or .A:90 or .A:92 or .A:98 or .A:102; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
VAL49
2.381
VAL52
3.698
MET53
2.152
LEU56
2.959
GLY57
2.502
ILE60
2.339
MET61
2.400
TYR66
2.711
GLN71
2.651
Residue
Distance (Å)
HIS72
2.414
MET73
4.574
VAL74
2.559
LEU81
4.943
PHE90
2.655
VAL92
2.316
LEU98
2.182
LEU102
2.199
Ligand Name: Guanidine Ligand Info
Structure Description Crystal structure of human MDMX in complex with a 12-mer peptide inhibitor PDB:3EQY
Method X-ray diffraction Resolution 1.63 Å Mutation Yes [6]
PDB Sequence
NQVRPKLPLL
34
KILHAAGAQG
44
EMFTVKEVMH
54
YLGQYIMVKQ
64
LYDAAAQHMV
74

YCGGDLLGEL
84
LGRQSFSVKD
94
PSPLYDMLRK
104
NLVT
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .GAI or .GAI2 or .GAI3 or :3GAI;style chemicals stick;color identity;select .A:38 or .A:42 or .A:43 or .A:44 or .A:45; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
HIS38
3.346
ALA42
4.507
GLN43
3.755
Residue
Distance (Å)
GLY44
3.033
GLU45
2.671
References  Top
REF 1 Structural States of Hdm2 and HdmX: X-ray Elucidation of Adaptations and Binding Interactions for Different Chemical Compound Classes. ChemMedChem. 2019 Jul 17;14(14):1305-1314.
REF 2 Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization. Proc Natl Acad Sci U S A. 2012 Jul 17;109(29):11788-93.
REF 3 Crystal structure of the N-terminal domain of human MdmX protein in complex with Nutlin3a
REF 4 Structures of low molecular weight inhibitors bound to MDMX and MDM2 reveal new approaches for p53-MDMX/MDM2 antagonist drug discovery. Cell Cycle. 2010 Mar 15;9(6):1104-11.
REF 5 Monitoring Ligand-Induced Protein Ordering in Drug Discovery. J Mol Biol. 2016 Mar 27;428(6):1290-1303.
REF 6 Structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX. Proc Natl Acad Sci U S A. 2009 Mar 24;106(12):4665-70.

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