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 T06273 Target Info
Target Name Poly [ADP-ribose] polymerase 1 (PARP1)
Synonyms Protein poly-ADP-ribosyltransferase PARP1; Poly[ADP-ribose] synthetase-1; Poly[ADP-ribose] synthase 1; Poly(ADP-ribose)polymerase-1; PPOL; PARP-1; NAD(+)Poly [ADP-ribose] polymerase-1 ADP-ribosyltransferase-1; NAD(+) ADP-ribosyltransferase-1; NAD(+) ADP-ribosyltransferase 1; DNA ADP-ribosyltransferase PARP1; ARTD1; ADPRT 1; ADPRT; ADP-ribosyltransferase diphtheria toxin-like 1
Target Type Successful Target
Gene Name PARP1
Biochemical Class Glycosyltransferases
UniProt ID
PARP1_HUMAN
Ligand General Information  Top
Ligand Name Olaparib Ligand Info
Canonical SMILES C1CC1C(=O)N2CCN(CC2)C(=O)C3=C(C=CC(=C3)CC4=NNC(=O)C5=CC=CC=C54)F
InChI 1S/C24H23FN4O3/c25-20-8-5-15(14-21-17-3-1-2-4-18(17)22(30)27-26-21)13-19(20)24(32)29-11-9-28(10-12-29)23(31)16-6-7-16/h1-5,8,13,16H,6-7,9-12,14H2,(H,27,30)
InChIKey FDLYAMZZIXQODN-UHFFFAOYSA-N
PubChem Compound ID 23725625
Drug Binding Sites of Target  Top
PDB ID: 7KK4      Structure of the catalytic domain of PARP1 in complex with olaparib
Method X-ray diffraction Resolution 1.96 Å Mutation No [1]
PDB Sequence
KSKLPKPVQD
671
LIKMIFDVES
681
MKKAMVEYEI
691
DLQKMPLGKL
701
SKRQIQAAYS
711

ILSEVQQAVS
721
QGSSDSQILD
731
LSNRFYTLIP
741
HDFPPLLNNA
755
DSVQAKVEML
765

DNLLDIEVAY
775
SLLRGSKDPI
790
DVNYEKLKTD
800
IKVVDRDSEE
810
AEIIRKYVKN
820

THATTHNAYD
830
LEVIDIFKIE
840
REGECQRYKP
850
FKQLHNRRLL
860
WHGSRTTNFA
870

GILSQGLRIA
880
PPEAPVTGYM
890
FGKGIYFADM
900
VSKSANYCHT
910
SQGDPIGLIL
920

LGEVALGNMY
930
ELKHASHISK
940
LPKGKHSVKG
950
LGKTTPDPSA
960
NISLDGVDVP
970

LGTGISSGVN
980
DTSLLYNEYI
990
VYDIAQVNLK
1000
YLLKLKFNFK
1010
Residue
Distance (Å)
TYR710
3.472
ASP766
3.307
LEU769
3.681
ASP770
4.048
TRP861
3.770
HIS862
3.294
GLY863
2.800
ARG878
2.978
ILE879
4.112
ALA880
3.698
PRO881
3.728
Residue
Distance (Å)
TYR889
3.317
GLY892
4.472
GLY894
3.692
ILE895
3.653
TYR896
3.041
PHE897
3.639
ALA898
3.827
LYS903
3.891
SER904
2.612
TYR907
3.386
GLU988
3.798
PDB ID: 7AAD      Crystal structure of the catalytic domain of human PARP1 in complex with olaparib
Method X-ray diffraction Resolution 2.21 Å Mutation Yes [2]
PDB Sequence
KSKLPKPVQD
671
LIKMIFDVES
681
MKKAMVEYEI
691
DLQKMPLGKL
701
SKRQIQAAYS
711

ILSEVQQAVS
721
QGSSDSQILD
731
LSNRFYTLIP
741
HDFGMKKPPL
751
LNNADSVQAK
761

AEMLDNLLDI
771
EVAYSLLRGG
781
SDDSSKDPID
791
VNYEKLKTDI
801
KVVDRDSEEA
811

EIIRKYVKNT
821
HATTHNAYDL
831
EVIDIFKIER
841
EGECQRYKPF
851
KQLHNRRLLW
861

HGSRTTNFAG
871
ILSQGLRIAP
881
PEAPVTGYMF
891
GKGIYFADMV
901
SKSANYCHTS
911

QGDPIGLILL
921
GEVALGNMYE
931
LKHASHISKL
941
PKGKHSVKGL
951
GKTTPDPSAN
961

ISLDGVDVPL
971
GTGISSGVND
981
TSLLYNEYIV
991
YDIAQVNLKY
1001
LLKLKFNFKT
1011
Residue
Distance (Å)
TYR710
4.139
ASP766
3.287
LEU769
3.795
ASP770
3.718
TRP861
3.899
HIS862
3.289
GLY863
2.867
LEU877
4.670
ARG878
3.212
ILE879
4.047
ALA880
3.788
PRO881
4.169
Residue
Distance (Å)
TYR889
3.388
GLY892
4.595
GLY894
3.330
ILE895
3.604
TYR896
2.811
PHE897
3.272
ALA898
3.792
LYS903
3.954
SER904
2.716
TYR907
3.302
GLU988
3.663
PDB ID: 5DS3      Crystal structure of constitutively active PARP-1
Method X-ray diffraction Resolution 2.60 Å Mutation No [3]
PDB Sequence
SKLPKPVQDL
774
IKMIFGSGSG
784
SGGDPIDVNY
794
EKLKTDIKVV
804
DRDSEEAEII
814

RKYVKNTHHN
827
AYDLEVIDIF
837
KIEREGECQR
847
YKPFKQLHNR
857
RLLWHGSRTT
867

NFAGILSQGL
877
RIAPPEAPVT
887
GYMFGKGIYF
897
ADMVSKSANY
907
CHTSQGDPIG
917

LILLGEVALG
927
NMYELKHASH
937
ISKLPKGKHS
947
VKGLGKTTPD
957
PSANISLDGV
967

DVPLGTGISS
977
GVNDTSLLYN
987
EYIVYDIAQV
997
NLKYLLKLKF
1007
NFK
Residue
Distance (Å)
TRP861
3.778
HIS862
3.145
GLY863
2.812
SER864
4.984
GLY876
4.434
LEU877
3.583
ARG878
2.892
ILE879
4.308
ALA880
4.037
GLY888
3.876
TYR889
3.358
Residue
Distance (Å)
GLY892
4.824
GLY894
3.236
ILE895
3.489
TYR896
2.828
PHE897
3.577
ALA898
4.045
LYS903
3.781
SER904
2.774
TYR907
3.153
GLU988
3.646
References  Top
REF 1 Dissecting the molecular determinants of clinical PARP1 inhibitor selectivity for tankyrase1. J Biol Chem. 2021 Jan-Jun;296:100251.
REF 2 Dynamics of the HD regulatory subdomain of PARP-1; substrate access and allostery in PARP activation and inhibition. Nucleic Acids Res. 2021 Feb 26;49(4):2266-2288.
REF 3 PARP-1 Activation Requires Local Unfolding of an Autoinhibitory Domain. Mol Cell. 2015 Dec 3;60(5):755-768.

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