Binding Site Information of Target
| Target General Information | Top | ||||
|---|---|---|---|---|---|
| Target ID | T63816 | Target Info | |||
| Target Name | Histone deacetylase 4 (HDAC4) | ||||
| Synonyms | KIAA0288; HD4 | ||||
| Target Type | Clinical trial Target | ||||
| Gene Name | HDAC4 | ||||
| Biochemical Class | Carbon-nitrogen hydrolase | ||||
| UniProt ID | |||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| Ligand Name: PMID29671355-Compound-47a | Ligand Info | |||||
| Structure Description | Potent, selective and CNS-penetrant tetrasubstituted cyclopropane class IIa histone deacetylase (HDAC) inhibitors | PDB:5A2S | ||||
| Method | X-ray diffraction | Resolution | 2.65 Å | Mutation | Yes | [1] |
| PDB Sequence |
TTGLVYDTLM
662 LKHQCTCGSS672 SSHPEHAGRI682 QSIWSRLQET692 GLRGKCECIR702 GRKATLEELQ 712 TVHSEAHTLL722 YGTNPANRQK732 LDSKKLLGSL742 ASVFVRLPCG752 GVGVDSDTIW 762 NEVHSAGAAR772 LAVGCVVELV782 FKVATGELKN792 GFAVVRPPGH802 HAEESTPMGF 812 CYFNSVAVAA822 KLLQQRLSVS832 KILIVDWDVH842 HGNGTQQAFY852 SDPSVLYMSL 862 HRYDDGNFFP872 GSGAPDEVGT882 GPGVGFNVNM892 AFTGGLDPPM902 GDAEYLAAFR 912 TVVMPIASEF922 APDVVLVSSG932 FDAVEGHPTP942 LGGYNLSARC952 FGYLTKQLMG 962 LAGGRIVLAL972 EGGHDLTAIC982 DASEACVSAL992 LGNELDPLPE1002 KVLQQRPNAN 1012 AVRSMEKVME1022 IHSKYWRCLQ1032
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| Ligand Name: N-Hydroxy-5-[(3-Phenyl-5,6-Dihydroimidazo[1,2-A]pyrazin-7(8h)-Yl)carbonyl]thiophene-2-Carboxamide | Ligand Info | |||||
| Structure Description | Structure of HDAC4 catalytic domain bound to a hydroxamic acid inhbitor | PDB:2VQM | ||||
| Method | X-ray diffraction | Resolution | 1.80 Å | Mutation | No | [2] |
| PDB Sequence |
PRFTTGLVYD
15 TLMLKHQCTC25 GHAGRIQSIW42 SRLQETGLRG52 KCECIRGRKA62 TLEELQTVHS 72 EAHTLLYGTN82 PLNRQKKLLG96 SLASVFVRLP106 CGGVGVDSDT116 IWNEVHSAGA 126 ARLAVGCVVE136 LVFKVATGEL146 KNGFAVVRPP156 GHHAEESTPM166 GFCYFNSVAV 176 AAKLLQQRLS186 VSKILIVDWD196 VHHGNGTQQA206 FYSDPSVLYM216 SLHRYDDGNF 226 FPGSGAPDEV236 GTGPGVGFNV246 NMAFTGGLDP256 PMGDAEYLAA266 FRTVVMPIAS 276 EFAPDVVLVS286 SGFDAVEGHP296 TPLGGYNLSA306 RCFGYLTKQL316 MGLAGGRIVL 326 ALEGGHDLTA336 ICDASEACVS346 ALLGNELDPL356 PEKVLQQRPN366 ANAVRSMEKV 376 MEIHSKYWRC386 LQRTTSTAGR396 SLIEAQTCEN406 E
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: 2,2,2-Trifluoro-1-{5-[(3-Phenyl-5,6-Dihydroimidazo[1,2-A]pyrazin-7(8h)-Yl)carbonyl]thiophen-2-Yl}ethane-1,1-Diol | Ligand Info | |||||
| Structure Description | Structure of HDAC4 catalytic domain (a double cysteine-to-alanine mutant) bound to a trifluoromethylketone inhbitor | PDB:2VQQ | ||||
| Method | X-ray diffraction | Resolution | 1.90 Å | Mutation | Yes | [2] |
| PDB Sequence |
RFTTGLVYDT
16 LMLKHQHAGR37 IQSIWSRLQE47 TGLRGKCEAI57 RGRKATLEEL67 QTVHSEAHTL 77 LYGTNPLVDS114 DTIWNEVHSA124 GAARLAVGCV134 VELVFKVATG144 ELKNGFAVVR 154 PPGHHAEEST164 PMGFCYFNSV174 AVAAKLLQQR184 LSVSKILIVD194 WDVHHGNGTQ 204 QAFYSDPSVL214 YMSLHRYDDG224 NFFPGSGAPD234 EVGTGPGVGF244 NVNMAFTGGL 254 DPPMGDAEYL264 AAFRTVVMPI274 ASEFAPDVVL284 VSSGFDAVEG294 HPTPLGGYNL 304 SARCFGYLTK314 QLMGLAGGRI324 VLALEGGHDL334 TAICDASEAC344 VSALLGNELD 354 PLPEKVLQQR364 PNANAVRSME374 KVMEIHSKYW384 RCLQRTTSTA394 GRSLIEAQTC 404 E
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .TFG or .TFG2 or .TFG3 or :3TFG;style chemicals stick;color identity;select .A:156 or .A:158 or .A:159 or .A:167 or .A:168 or .A:169 or .A:196 or .A:198 or .A:227 or .A:290 or .A:298 or .A:299 or .A:329 or .A:330 or .A:331; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: (2~{S})-2-(2-fluorophenyl)-2-[4-(2-methylpyrimidin-5-yl)phenyl]-~{N}-oxidanyl-ethanamide | Ligand Info | |||||
| Structure Description | Development and characterization of a CNS-penetrant benzhydryl hydroxamic acid class IIa histone deacetylase inhibitor | PDB:6FYZ | ||||
| Method | X-ray diffraction | Resolution | 2.15 Å | Mutation | No | [3] |
| PDB Sequence |
PRFTTGLVYD
659 TLMLKHQCTC669 GSSSSHPEHA679 GRIQSIWSRL689 QETGLRGKCE699 CIRGRKATLE 709 ELQTVHSEAH719 TLLYGTNPLI761 WNEVHSAGAA771 RLAVGCVVEL781 VFKVATGELK 791 NGFAVVRPPG801 HHAEESTPMG811 FCYFNSVAVA821 AKLLQQRLSV831 SKILIVDWDV 841 HHGNGTQQAF851 YSDPSVLYMS861 LHRYDDGNFF871 PGSGAPDEVG881 TGPGVGFNVN 891 MAFTGGLDPP901 MGDAEYLAAF911 RTVVMPIASE921 FAPDVVLVSS931 GFDAVEGHPT 941 PLGGYNLSAR951 CFGYLTKQLM961 GLAGGRIVLA971 LEGGHDLTAI981 CDASEACVSA 991 LLGNELQQRP1009 NANAVRSMEK1019 VMEIHSKYWR1029 CLQRH
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .EBE or .EBE2 or .EBE3 or :3EBE;style chemicals stick;color identity;select .A:676 or .A:677 or .A:681 or .A:800 or .A:802 or .A:803 or .A:811 or .A:812 or .A:840 or .A:842 or .A:871 or .A:934 or .A:942 or .A:943 or .A:973 or .A:974 or .A:975 or .A:976; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| Ligand Name: (1r,2r,3r)-2-[4-(1,3-Oxazol-5-Yl)phenyl]-N-Oxidanyl-3-Phenyl-Cyclopropane-1-Carboxamide | Ligand Info | |||||
| Structure Description | Design, synthesis, and biological evaluation of potent and selective Class IIa HDAC inhibitors as a potential therapy for Huntington's disease | PDB:4CBY | ||||
| Method | X-ray diffraction | Resolution | 2.72 Å | Mutation | Yes | [4] |
| PDB Sequence |
TTGLVYDTLM
662 LKHQCTCGSS672 SSHPEHAGRI682 QSIWSRLQET692 GLRGKCECIR702 GRKATLEELQ 712 TVHSEAHTLL722 YGTNPANRQK732 LDSKKLLGSL742 ASVFVRLPCG752 GVGVDSDTIW 762 NEVHSAGAAR772 LAVGCVVELV782 FKVATGELKN792 GFAVVRPPGH802 HAEESTPMGF 812 CYFNSVAVAA822 KLLQQRLSVS832 KILIVDWDVH842 HGNGTQQAFY852 SDPSVLYMSL 862 HRYDDGNFFP872 GSGAPDEVGT882 GPGVGFNVNM892 AFTGGLDPPM902 GDAEYLAAFR 912 TVVMPIASEF922 APDVVLVSSG932 FDAVEGHPTP942 LGGYNLSARC952 FGYLTKQLMG 962 LAGGRIVLAL972 EGGHDLTAIC982 DASEACVSAL992 LGNELDPLPE1002 KVLQQRPNAN 1012 AVRSMEKVME1022 IHSKYWRCLQ1032
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .KEE or .KEE2 or .KEE3 or :3KEE;style chemicals stick;color identity;select .A:676 or .A:677 or .A:681 or .A:800 or .A:802 or .A:803 or .A:811 or .A:812 or .A:840 or .A:842 or .A:871 or .A:934 or .A:942 or .A:943 or .A:973 or .A:974 or .A:975 or .A:976; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| Ligand Name: (1r,2r,3r)-2-[4-(5-Fluoranylpyrimidin-2-Yl)phenyl]-N-Oxidanyl-3-Phenyl-Cyclopropane-1-Carboxamide | Ligand Info | |||||
| Structure Description | Design, synthesis, and biological evaluation of potent and selective Class IIa HDAC inhibitors as a potential therapy for Huntington's disease | PDB:4CBT | ||||
| Method | X-ray diffraction | Resolution | 3.03 Å | Mutation | No | [4] |
| PDB Sequence |
PRFTTGLVYD
659 TLMLKHQCTC669 GSSSSHPEHA679 GRIQSIWSRL689 QETGLRGKCE699 CIRGRKATLE 709 ELQTVHSEAH719 TLLYGTNPLS758 DTIWNEVHSA768 GAARLAVGCV778 VELVFKVATG 788 ELKNGFAVVR798 PPGHHAEEST808 PMGFCYFNSV818 AVAAKLLQQR828 LSVSKILIVD 838 WDVHHGNGTQ848 QAFYSDPSVL858 YMSLHRYDDG868 NFFPGSGAPD878 EVGTGPGVGF 888 NVNMAFTGGL898 DPPMGDAEYL908 AAFRTVVMPI918 ASEFAPDVVL928 VSSGFDAVEG 938 HPTPLGGYNL948 SARCFGYLTK958 QLMGLAGGRI968 VLALEGGHDL978 TAICDASEAC 988 VSALLGNELL1005 QQRPNANAVR1015 SMEKVMEIHS1025 KYWRCLQRH
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .9F4 or .9F42 or .9F43 or :39F4;style chemicals stick;color identity;select .A:676 or .A:677 or .A:681 or .A:800 or .A:802 or .A:803 or .A:811 or .A:812 or .A:840 or .A:842 or .A:871 or .A:934 or .A:942 or .A:943 or .A:973 or .A:974 or .A:975 or .A:976; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| References | Top | ||||
|---|---|---|---|---|---|
| REF 1 | Potent, Selective, and CNS-Penetrant Tetrasubstituted Cyclopropane Class IIa Histone Deacetylase (HDAC) Inhibitors. ACS Med Chem Lett. 2015 Dec 10;7(1):34-9. | ||||
| REF 2 | Structural and functional analysis of the human HDAC4 catalytic domain reveals a regulatory structural zinc-binding domain. J Biol Chem. 2008 Sep 26;283(39):26694-704. | ||||
| REF 3 | Development and characterization of a CNS-penetrant benzhydryl hydroxamic acid class IIa histone deacetylase inhibitor. Bioorg Med Chem Lett. 2019 Jan 1;29(1):83-88. | ||||
| REF 4 | Design, synthesis, and biological evaluation of potent and selective class IIa histone deacetylase (HDAC) inhibitors as a potential therapy for Huntington's disease. J Med Chem. 2013 Dec 27;56(24):9934-54. | ||||
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