Binding Site Information of Target

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Target General Information
Drug Binding Sites of Target
References
Target General Information  Top
Target ID T13176 Target Info
Target Name PRKR-like endoplasmic reticulum kinase (PERK)
Synonyms PEK
Target Type Clinical trial Target
Gene Name EIF2AK3
Biochemical Class Kinase
UniProt ID
E2AK3_HUMAN
Drug Binding Sites of Target  Top
Ligand Name: GSK2606414 Ligand Info
Structure Description Crystal Structure of GSK6414 Bound to PERK (R587-R1092, delete A660-T867) at 2.28 A Resolution PDB:4G31
Method X-ray diffraction Resolution 2.28 Å Mutation No [1]
PDB Sequence
GRYLTDFEPI
595
QCLGRGGVVF
607
EAKNKVDDCN
617
YAIKRIRLPN
627
RELAREKVMR
637

EVKALAKLEH
647
PGIVRYFNAW
657
LEKNKVYLYI
885
QMQLCRKENL
895
KDWMNGRCTI
905

EERERSVCLH
915
IFLQIAEAVE
925
FLHSKGLMHR
935
DLKPSNIFFT
945
MDDVVKVGDF
955

GLVGTKLYMS
991
PEQIHGNSYS
1001
HKVDIFSLGL
1011
ILFELLYPFS
1021
TQMERVRTLT
1031

DVRNLKFPPL
1041
FTQKYPCEYV
1051
MVQDMLSPSP
1061
MERPEAINII
1071
ENAVFEDL
Residue
Distance (Å)
LEU598
3.817
GLY599
4.990
VAL606
3.923
ALA619
3.389
LYS621
3.877
GLU638
4.609
VAL639
3.402
LEU642
3.534
ALA643
3.169
ILE650
4.436
VAL651
3.637
TYR653
3.393
ALA656
4.583
Residue
Distance (Å)
ILE885
3.202
MET887
3.622
GLN888
2.819
LEU889
3.753
CYS890
2.791
ARG891
4.560
PHE943
3.475
VAL952
4.956
GLY953
3.674
ASP954
3.061
PHE955
3.499
LEU957
4.261
Ligand Name: 4-{2-Amino-3-[5-Fluoro-2-(Methylamino)quinazolin-6-Yl]-4-Methylbenzoyl}-1-Methyl-2,5-Diphenyl-1,2-Dihydro-3h-Pyrazol-3-One Ligand Info
Structure Description Co-crystal Structure of PERK bound to 4-{2-amino-3-[5-fluoro-2-(methylamino)quinazolin-6-yl]-4-methylbenzoyl}-1-methyl-2,5-diphenyl-1,2-dihydro-3H-pyrazol-3-one inhibitor PDB:4X7K
Method X-ray diffraction Resolution 1.80 Å Mutation Yes [2]
PDB Sequence
YISRYLTDFE
594
PIQCLGRGGF
604
GVVFEAKNKV
614
DDCNYAIKRI
624
RLPNRELARE
634

KVMREVKALA
644
KLEHPGIVRY
654
FNAWLEAPPK
881
VYLYIQMQLC
891
RKENLKDWMN
901

GRCTIEERER
911
SVCLHIFLQI
921
AEAVEFLHSK
931
GLMHRNLKPS
941
NIFFTMDDVV
951

KVGDFGLVTT
987
KLYMSPEQIH
997
GNSYSHKVDI
1007
FSLGLILFEL
1017
LYPFSTQMER
1027

VRTLTDVRNL
1037
KFPPLFTQKY
1047
PCEYVMVQDM
1057
LSPSPMERPE
1067
AINIIENAVF
1077

EDLDFPGKTV
1087
Residue
Distance (Å)
LEU599
3.904
VAL607
3.675
ALA620
3.402
ILE621
4.021
LYS622
2.729
ILE624
3.790
VAL636
4.009
GLU639
3.208
VAL640
4.542
LEU643
3.522
LEU646
4.185
ILE651
3.797
VAL652
3.448
ILE886
3.663
Residue
Distance (Å)
MET888
3.252
GLN889
3.417
LEU890
3.861
CYS891
2.865
ARG892
3.689
LYS893
3.852
LEU928
4.917
HIS935
4.569
PHE944
4.134
VAL953
4.249
GLY954
3.412
ASP955
2.783
PHE956
3.404
LEU958
4.017
Ligand Name: 4-{2-Amino-4-Methyl-3-[2-(Methylamino)-1,3-Benzothiazol-6-Yl]benzoyl}-1-Methyl-2,5-Diphenyl-1,2-Dihydro-3h-Pyrazol-3-One Ligand Info
Structure Description Co-crystal Structure of PERK bound to 4-{2-amino-4-methyl-3-[2-(methylamino)-1,3-benzothiazol-6-yl]benzoyl}-1-methyl-2,5-diphenyl-1,2-dihydro-3H-pyrazol-3-one inhibitor PDB:4X7L
Method X-ray diffraction Resolution 1.90 Å Mutation Yes [2]
PDB Sequence
YISRYLTDFE
594
PIQCLGRGGF
604
GVVFEAKNKV
614
DDCNYAIKRI
624
RLPNRELARE
634

KVMREVKALA
644
KLEHPGIVRY
654
FNAWLEAPPK
881
VYLYIQMQLC
891
RKENLKDWMN
901

GRCTIEERER
911
SVCLHIFLQI
921
AEAVEFLHSK
931
GLMHRNLKPS
941
NIFFTMDDVV
951

KVGDFGLVTT
987
KLYMSPEQIH
997
GNSYSHKVDI
1007
FSLGLILFEL
1017
LYPFSTQMER
1027

VRTLTDVRNL
1037
KFPPLFTQKY
1047
PCEYVMVQDM
1057
LSPSPMERPE
1067
AINIIENAVF
1077

EDLDFPGKTV
1087
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .3Z4 or .3Z42 or .3Z43 or :33Z4;style chemicals stick;color identity;select .A:599 or .A:607 or .A:620 or .A:621 or .A:622 or .A:624 or .A:636 or .A:639 or .A:640 or .A:643 or .A:646 or .A:651 or .A:652 or .A:884 or .A:886 or .A:888 or .A:889 or .A:890 or .A:891 or .A:892 or .A:893 or .A:928 or .A:935 or .A:944 or .A:953 or .A:954 or .A:955 or .A:956 or .A:958; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
LEU599
3.947
VAL607
3.975
ALA620
3.400
ILE621
4.042
LYS622
2.752
ILE624
3.760
VAL636
4.000
GLU639
3.249
VAL640
4.556
LEU643
3.550
LEU646
4.252
ILE651
3.797
VAL652
3.497
LEU884
4.962
ILE886
3.644
Residue
Distance (Å)
MET888
3.260
GLN889
3.264
LEU890
3.840
CYS891
2.934
ARG892
3.712
LYS893
3.916
LEU928
4.885
HIS935
4.548
PHE944
4.158
VAL953
4.275
GLY954
3.380
ASP955
2.728
PHE956
3.504
LEU958
3.900
Ligand Name: N-{5-[(6,7-Dimethoxyquinolin-4-Yl)oxy]pyridin-2-Yl}-1-Methyl-3-Oxo-2-Phenyl-5-(Pyridin-4-Yl)-2,3-Dihydro-1h-Pyrazole-4-Carboxamide Ligand Info
Structure Description Co-crystal Structure of PERK bound to N-{5-[(6,7-dimethoxyquinolin-4-yl)oxy]pyridin-2-yl}-1-methyl-3-oxo-2-phenyl-5-(pyridin-4-yl)-2,3-dihydro-1H-pyrazole-4-carboxamide inhibitor PDB:4X7H
Method X-ray diffraction Resolution 2.00 Å Mutation Yes [2]
PDB Sequence
YISRYLTDFE
594
PIQCLGRGGF
604
GVVFEAKNKV
614
DDCNYAIKRI
624
RLPNRELARE
634

KVMREVKALA
644
KLEHPGIVRY
654
FNAWLEAPPK
881
VYLYIQMQLC
891
RKENLKDWMN
901

GRCTIEERER
911
SVCLHIFLQI
921
AEAVEFLHSK
931
GLMHRNLKPS
941
NIFFTMDDVV
951

KVGDFGTKLY
990
MSPEQIHGNS
1000
YSHKVDIFSL
1010
GLILFELLYP
1020
FSTQMERVRT
1030

LTDVRNLKFP
1040
PLFTQKYPCE
1050
YVMVQDMLSP
1060
SPMERPEAIN
1070
IIENAVFEDL
1080

DFPGKT
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .3Z2 or .3Z22 or .3Z23 or :33Z2;style chemicals stick;color identity;select .A:599 or .A:600 or .A:607 or .A:620 or .A:622 or .A:624 or .A:636 or .A:639 or .A:640 or .A:643 or .A:646 or .A:651 or .A:652 or .A:884 or .A:886 or .A:888 or .A:889 or .A:890 or .A:891 or .A:892 or .A:893 or .A:928 or .A:935 or .A:944 or .A:953 or .A:954 or .A:955 or .A:956 or .A:957; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
LEU599
3.429
GLY600
4.288
VAL607
3.984
ALA620
3.402
LYS622
3.073
ILE624
3.951
VAL636
3.821
GLU639
3.144
VAL640
4.002
LEU643
3.707
LEU646
4.709
ILE651
4.101
VAL652
4.553
LEU884
4.651
ILE886
3.523
Residue
Distance (Å)
MET888
3.374
GLN889
3.124
LEU890
3.774
CYS891
2.831
ARG892
3.756
LYS893
3.497
LEU928
4.759
HIS935
3.576
PHE944
3.473
VAL953
3.784
GLY954
3.266
ASP955
2.759
PHE956
3.551
GLY957
4.503
Ligand Name: 2-Amino-N-[4-Methoxy-3-(Trifluoromethyl)phenyl]-4-Methyl-3-[2-(Methylamino)quinazolin-6-Yl]benzamide Ligand Info
Structure Description Co-crystal Structure of PERK with 2-amino-N-[4-methoxy-3-(trifluoromethyl)phenyl]-4-methyl-3-[2-(methylamino)quinazolin-6-yl]benzamide inhibitor PDB:4X7J
Method X-ray diffraction Resolution 2.30 Å Mutation Yes [2]
PDB Sequence
YISRYLTDFE
594
PIQCLGRGGF
604
GVVFEAKNKV
614
DDCNYAIKRI
624
RLPNRELARE
634

KVMREVKALA
644
KLEHPGIVRY
654
FNAWLEAPPK
881
VYLYIQMQLC
891
RKENLKDWMN
901

GRCTIEERER
911
SVCLHIFLQI
921
AEAVEFLHSK
931
GLMHRNLKPS
941
NIFFTMDDVV
951

KVGDFGLVKL
989
YMSPEQIHGN
999
SYSHKVDIFS
1009
LGLILFELLY
1019
PFSTQMERVR
1029

TLTDVRNLKF
1039
PPLFTQKYPC
1049
EYVMVQDMLS
1059
PSPMERPEAI
1069
NIIENAVFED
1079

LDFPGKT
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .3Z1 or .3Z12 or .3Z13 or :33Z1;style chemicals stick;color identity;select .A:599 or .A:607 or .A:620 or .A:621 or .A:622 or .A:639 or .A:642 or .A:643 or .A:646 or .A:651 or .A:652 or .A:886 or .A:888 or .A:889 or .A:890 or .A:891 or .A:892 or .A:893 or .A:928 or .A:933 or .A:935 or .A:944 or .A:953 or .A:954 or .A:955 or .A:956 or .A:958; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
LEU599
4.003
VAL607
3.684
ALA620
3.430
ILE621
4.124
LYS622
3.374
GLU639
4.061
ALA642
3.998
LEU643
3.730
LEU646
3.125
ILE651
4.153
VAL652
4.284
ILE886
3.823
MET888
3.321
GLN889
3.239
Residue
Distance (Å)
LEU890
3.826
CYS891
2.836
ARG892
3.870
LYS893
3.907
LEU928
3.554
LEU933
3.830
HIS935
4.192
PHE944
3.998
VAL953
3.887
GLY954
3.356
ASP955
2.705
PHE956
3.363
LEU958
4.051
Ligand Name: 4-[2-Amino-4-Methyl-3-(2-Methylquinolin-6-Yl)benzoyl]-1-Methyl-2,5-Diphenyl-1,2-Dihydro-3h-Pyrazol-3-One Ligand Info
Structure Description Co-crystal Structure of PERK bound to 4-[2-amino-4-methyl-3-(2-methylquinolin-6-yl)benzoyl]-1-methyl-2,5-diphenyl-1,2-dihydro-3H-pyrazol-3-one inhibitor PDB:4X7N
Method X-ray diffraction Resolution 2.35 Å Mutation Yes [2]
PDB Sequence
YISRYLTDFE
594
PIQCLGRGGF
604
GVVFEAKNKV
614
DDCNYAIKRI
624
RLPNRELARE
634

KVMREVKALA
644
KLEHPGIVRY
654
FNAWLEAPKV
882
YLYIQMQLCR
892
KENLKDWMNG
902

RCTIEERERS
912
VCLHIFLQIA
922
EAVEFLHSKG
932
LMHRNLKPSN
942
IFFTMDDVVK
952

VGDFGLVTTK
988
LYMSPEQIHG
998
NSYSHKVDIF
1008
SLGLILFELL
1018
YPFSTQMERV
1028

RTLTDVRNLK
1038
FPPLFTQKYP
1048
CEYVMVQDML
1058
SPSPMERPEA
1068
INIIENAVFE
1078

DLDFPGKTV
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .3Z5 or .3Z52 or .3Z53 or :33Z5;style chemicals stick;color identity;select .A:599 or .A:607 or .A:620 or .A:621 or .A:622 or .A:624 or .A:636 or .A:639 or .A:640 or .A:643 or .A:646 or .A:651 or .A:652 or .A:884 or .A:886 or .A:888 or .A:889 or .A:890 or .A:891 or .A:892 or .A:893 or .A:928 or .A:935 or .A:944 or .A:953 or .A:954 or .A:955 or .A:956 or .A:958; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
LEU599
3.806
VAL607
3.795
ALA620
3.360
ILE621
3.900
LYS622
2.707
ILE624
3.827
VAL636
4.074
GLU639
3.260
VAL640
4.475
LEU643
3.403
LEU646
4.289
ILE651
3.849
VAL652
3.538
LEU884
4.919
ILE886
3.628
Residue
Distance (Å)
MET888
3.247
GLN889
3.319
LEU890
3.892
CYS891
3.355
ARG892
3.463
LYS893
4.245
LEU928
4.928
HIS935
4.578
PHE944
3.932
VAL953
4.179
GLY954
3.405
ASP955
2.748
PHE956
3.454
LEU958
4.130
Ligand Name: 1-[5-(4-Amino-2,7-Dimethyl-7h-Pyrrolo[2,3-D]pyrimidin-5-Yl)-2,3-Dihydro-1h-Indol-1-Yl]-2-[3-Fluoro-5-(Trifluoromethyl)phenyl]ethanone Ligand Info
Structure Description Co-crystal Structure of PERK bound to 1-[5-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydro-1H-indol-1-yl]-2-[3-fluoro-5-(trifluoromethyl)phenyl]ethanone inhibitor PDB:4X7O
Method X-ray diffraction Resolution 2.65 Å Mutation Yes [2]
PDB Sequence
YISRYLTDFE
594
PIQCLGRGGV
606
VFEAKNKVDD
616
CNYAIKRIRL
626
PNRELAREKV
636

MREVKALAKL
646
EHPGIVRYFN
656
AWLEAPPKVY
883
LYIQMQLCRK
893
ENLKDWMNGR
903

CTIEERERSV
913
CLHIFLQIAE
923
AVEFLHSKGL
933
MHRNLKPSNI
943
FFTMDDVVKV
953

GDFGTKLYMS
992
PEQIHYSHKV
1005
DIFSLGLILF
1015
ELLYPFSTQM
1025
ERVRTLTDVR
1035

NLKFPPLFTQ
1045
KYPCEYVMVQ
1055
DMLSPSPMER
1065
PEAINIIENA
1075
VFEDLD
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .3Z6 or .3Z62 or .3Z63 or :33Z6;style chemicals stick;color identity;select .A:599 or .A:600 or .A:607 or .A:620 or .A:622 or .A:639 or .A:640 or .A:643 or .A:644 or .A:646 or .A:651 or .A:652 or .A:654 or .A:657 or .A:886 or .A:888 or .A:889 or .A:890 or .A:891 or .A:892 or .A:893 or .A:944 or .A:953 or .A:954 or .A:955 or .A:956; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
LEU599
3.801
GLY600
4.412
VAL607
3.982
ALA620
3.647
LYS622
3.847
GLU639
4.888
VAL640
3.296
LEU643
3.131
ALA644
3.332
LEU646
3.779
ILE651
3.883
VAL652
3.327
TYR654
3.379
Residue
Distance (Å)
ALA657
4.758
ILE886
3.203
MET888
3.461
GLN889
2.933
LEU890
3.780
CYS891
3.082
ARG892
3.569
LYS893
4.924
PHE944
3.703
VAL953
4.960
GLY954
3.853
ASP955
3.235
PHE956
3.730
Ligand Name: 1-[5-(4-Amino-7-Methyl-7h-Pyrrolo[2,3-D]pyrimidin-5-Yl)-4-Fluoro-1h-Indol-1-Yl]-2-(6-Methylpyridin-2-Yl)ethanone Ligand Info
Structure Description Crystal Structure of GSK6157 Bound to PERK (R587-R1092, delete A660-T867) at 2.34A Resolution PDB:4M7I
Method X-ray diffraction Resolution 2.34 Å Mutation No [3]
PDB Sequence
GRYLTDFEPI
595
QCLGRFGVVF
607
EAKNKVDDCN
617
YAIKRIRLPN
627
RELAREKVMR
637

EVKALAKLEH
647
PGIVRYFNAW
657
LEKKVYLYIQ
886
MQLCRKENLK
896
DWMNGRCTIE
906

ERERSVCLHI
916
FLQIAEAVEF
926
LHSKGLMHRD
936
LKPSNIFFTM
946
DDVVKVGDFG
956

LVGTKLYMSP
992
EQIHGNSYSH
1002
KVDIFSLGLI
1012
LFELLYPFST
1022
QMERVRTLTD
1032

VRNLKFPPLF
1042
TQKYPCEYVM
1052
VQDMLSPSPM
1062
ERPEAINIIE
1072
NAVFEDL
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .27D or .27D2 or .27D3 or :327D;style chemicals stick;color identity;select .A:598 or .A:599 or .A:606 or .A:619 or .A:621 or .A:639 or .A:642 or .A:643 or .A:650 or .A:651 or .A:653 or .A:885 or .A:887 or .A:888 or .A:889 or .A:890 or .A:891 or .A:943 or .A:952 or .A:953 or .A:954 or .A:955; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
LEU598
3.681
GLY599
4.914
VAL606
3.488
ALA619
3.458
LYS621
3.755
VAL639
4.242
LEU642
3.399
ALA643
3.765
ILE650
4.568
VAL651
3.636
TYR653
3.516
Residue
Distance (Å)
ILE885
3.823
MET887
3.745
GLN888
2.782
LEU889
3.733
CYS890
2.778
ARG891
4.482
PHE943
3.459
VAL952
4.787
GLY953
3.612
ASP954
2.990
PHE955
3.618
Ligand Name: 1-[5-(4-Aminothieno[3,2-C]pyridin-3-Yl)-2,3-Dihydro-1h-Indol-1-Yl]-2-Phenylethanone Ligand Info
Structure Description Crystal Structure of GSK6924 Bound to PERK (R587-R1092, delete A660-T867) at 2.70 A Resolution PDB:4G34
Method X-ray diffraction Resolution 2.70 Å Mutation No [1]
PDB Sequence
GRYLTDFEPI
595
QCLGRGGFGV
605
VFEAKNKVDD
615
CNYAIKRIRL
625
PNRELAREKV
635

MREVKALAKL
645
EHPGIVRYFN
655
AWLEKNKVYL
883
YIQMQLCRKE
893
NLKDWMNGRC
903

TIEERERSVC
913
LHIFLQIAEA
923
VEFLHSKGLM
933
HRDLKPSNIF
943
FTMDDVVKVG
953

DFGLGTKLYM
990
SPEQIHGNSY
1000
SHKVDIFSLG
1010
LILFELLYPF
1020
STQMERVRTL
1030

TDVRNLKFPP
1040
LFTQKYPCEY
1050
VMVQDMLSPS
1060
PMERPEAINI
1070
IENAVFED
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .924 or .9242 or .9243 or :3924;style chemicals stick;color identity;select .A:598 or .A:606 or .A:619 or .A:621 or .A:642 or .A:643 or .A:645 or .A:650 or .A:651 or .A:653 or .A:885 or .A:887 or .A:888 or .A:889 or .A:890 or .A:891 or .A:943 or .A:952 or .A:953 or .A:954 or .A:955; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
LEU598
3.798
VAL606
3.967
ALA619
3.559
LYS621
3.954
LEU642
3.225
ALA643
4.145
LEU645
4.565
ILE650
4.203
VAL651
3.666
TYR653
3.610
ILE885
4.322
Residue
Distance (Å)
MET887
3.562
GLN888
2.938
LEU889
3.776
CYS890
2.799
ARG891
4.562
PHE943
3.741
VAL952
4.789
GLY953
3.672
ASP954
3.389
PHE955
3.708
References  Top
REF 1 Discovery of 7-methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK). J Med Chem. 2012 Aug 23;55(16):7193-207.
REF 2 Discovery of 1H-pyrazol-3(2H)-ones as potent and selective inhibitors of protein kinase R-like endoplasmic reticulum kinase (PERK). J Med Chem. 2015 Feb 12;58(3):1426-41.
REF 3 Discovery of 5-{4-fluoro-1-[(6-methyl-2-pyridinyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (GSK2656157), a Potent and Selective PERK Inhibitor Selected for Preclinical Development

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