6FYZ: Histone deacetylase 4

Development and characterization of a CNS-penetrant benzhydryl hydroxamic acid class IIa histone deacetylase inhibitor. Determined by X-ray diffraction at 2.15 Å resolution. Released 5 Dec 2018.

Method: X-ray diffraction
Resolution: 2.15 Å
Organism: Homo sapiens
Chains: 3
Atoms: 8,256
Mol. weight: 129.87 kDa
Ligands: EBE, ZN
Released: 5 Dec 2018

Explore 6FYZ in 3D Show helices and sheets RCSB PDB PDBe

Secondary structure: helices and β-sheets

6FYZ contains 65 α-helices and 44 β-strands across 3 chains. Residue ranges use author residue numbering, as in the PDB file, from PDBe. To see them in 3D, choose the Cartoon representation with Secondary structure coloring: helices, sheets and coils get different colors.

Chain A: 21 helices, 14 β-strands

Element	Residues	Length	Sheet
β-strand	654-657	4	1
α-helix	660-664	5
α-helix	680-691	12
α-helix	695-697	3
β-strand	699-701	3	1
α-helix	705-707	3
α-helix	708-711	4
α-helix	717-724	8
α-helix	767-786	20
β-strand	792-795	4	1
β-strand	810	1	2
β-strand	813	1	2
α-helix	817-828	12
β-strand	834-838	5	1
α-helix	845-851	7
β-strand	857-864	8	1
α-helix	866-868	3
α-helix	883-885	3
β-strand	889-894	6	1
α-helix	901-902	2
β-strand	903	1	3
α-helix	904-910	7
α-helix	911-915	5
α-helix	916-922	7
β-strand	926-931	6	1
β-strand	936	1	4
β-strand	947	1	3
β-strand	948	1	4
α-helix	950-961	12
α-helix	964-966	3
β-strand	968-972	5	1
α-helix	978-992	15
α-helix	1007-1010	4
α-helix	1011-1024	14
α-helix	1029-1031	3

Chain B: 22 helices, 14 β-strands

Element	Residues	Length	Sheet
β-strand	654-657	4	5
α-helix	660-664	5
α-helix	680-691	12
β-strand	699-701	3	5
α-helix	705-707	3
α-helix	708-711	4
α-helix	717-724	8
β-strand	755-757	3	6
β-strand	760-761	2	6
α-helix	767-786	20
β-strand	792-795	4	5
β-strand	810	1	7
β-strand	813	1	7
α-helix	817-829	13
β-strand	834-838	5	5
α-helix	845-851	7
β-strand	857-864	8	5
α-helix	866-868	3
α-helix	883-885	3
β-strand	889-894	6	5
α-helix	901-902	2
α-helix	904-910	7
α-helix	911-915	5
α-helix	916-922	7
β-strand	926-931	6	5
β-strand	936	1	8
β-strand	948	1	8
α-helix	950-960	11
α-helix	964-966	3
β-strand	968-972	5	5
α-helix	978-993	16
α-helix	1000-1002	3
α-helix	1003-1006	4
α-helix	1008-1011	4
α-helix	1012-1025	14
α-helix	1030-1032	3

Chain C: 22 helices, 16 β-strands

Element	Residues	Length	Sheet
β-strand	654-657	4	9
α-helix	660-664	5
α-helix	680-691	12
α-helix	694-697	4
β-strand	699-701	3	9
α-helix	702	1
α-helix	705-707	3
α-helix	708-711	4
α-helix	717-724	8
α-helix	767-786	20
β-strand	792-795	4	9
β-strand	805	1	10
β-strand	808	1	10
β-strand	810	1	11
β-strand	813	1	11
α-helix	817-829	13
β-strand	834-838	5	9
α-helix	845-851	7
β-strand	857-864	8	9
α-helix	866-868	3
α-helix	883-885	3
β-strand	889-894	6	9
β-strand	903	1	12
α-helix	904-910	7
α-helix	911-915	5
α-helix	916-922	7
β-strand	926-931	6	9
β-strand	936	1	13
β-strand	947	1	12
β-strand	948	1	13
α-helix	950-961	12
α-helix	964-966	3
β-strand	968-972	5	9
α-helix	978-992	15
α-helix	1004-1006	3
α-helix	1008-1010	3
α-helix	1011-1024	14
α-helix	1029-1031	3

Molecules and chains

Molecule	Chains	Type	Length	Organism	UniProt
Histone deacetylase 4	A, B, C	protein	395	Homo sapiens	P56524 (AlphaFold model)

Sequence of entity 1 (A, B, C), FASTA

>6FYZ_1 Histone deacetylase 4 (chains A, B, C)
MGSTKPRFTTGLVYDTLMLKHQCTCGSSSSHPEHAGRIQSIWSRLQETGLRGKCECIRGR
KATLEELQTVHSEAHTLLYGTNPLNRQKLDSKKLLGSLASVFVRLPCGGVGVDSDTIWNE
VHSAGAARLAVGCVVELVFKVATGELKNGFAVVRPPGHHAEESTPMGFCYFNSVAVAAKL
LQQRLSVSKILIVDWDVHHGNGTQQAFYSDPSVLYMSLHRYDDGNFFPGSGAPDEVGTGP
GVGFNVNMAFTGGLDPPMGDAEYLAAFRTVVMPIASEFAPDVVLVSSGFDAVEGHPTPLG
GYNLSARCFGYLTKQLMGLAGGRIVLALEGGHDLTAICDASEACVSALLGNELDPLPEKV
LQQRPNANAVRSMEKVMEIHSKYWRCLQRHHHHHH

Ligands and cofactors

ID	Name	Formula	Copies
EBE	(2~{S})-2-(2-fluorophenyl)-2-[4-(2-methylpyrimidin-5-yl)phenyl]-~{N}-oxidanyl-e…	C19 H16 F N3 O2	3
ZN	Zinc ion	Zn	6

Water and common crystallization additives (NA) are not listed.

Primary citation

Development and characterization of a CNS-penetrant benzhydryl hydroxamic acid class IIa histone deacetylase inhibitor. Luckhurst, C.A., Aziz, O., Beaumont, V. et al. Bioorg Med Chem Lett (2019) 29:83-88. DOI 10.1016/j.bmcl.2018.11.009 · PubMed

Other PDB entries of the same protein (UniProt P56524 (AlphaFold model), which also has an AlphaFold model), best resolution first:

3V31 1.57 Å, Crystal Structure of the Peptide Bound Complex of the Ankyrin Repeat Domains of Human…
2VQM 1.8 Å, Structure of HDAC4 catalytic domain bound to a hydroxamic acid inhbitor
3UXG 1.85 Å, Crystal structure of RFXANK
5ZOO 1.85 Å, Crystal structure of histone deacetylase 4 (HDAC4) in complex with a SMRT corepressor…
3UZD 1.86 Å, Crystal structure of 14-3-3 GAMMA
2VQQ 1.9 Å, Structure of HDAC4 catalytic domain (a double cysteine-to-alanine mutant) bound to a…
2VQJ 2.1 Å, Structure of HDAC4 catalytic domain bound to a trifluoromethylketone inhbitor
2VQO 2.15 Å, Structure of HDAC4 catalytic domain with a gain-of-function muation bound to a…
8PDE 2.4 Å, Crystal Structure of the MADS-box/MEF2 Domain of MEF2D bound to dsDNA and HDAC4…
2H8N 2.6 Å, Structure of a glutamine-rich domain from histone deacetylase 4
5A2S 2.65 Å, Potent, selective and CNS-penetrant tetrasubstituted cyclopropane class IIa histone…
5ZOP 2.7 Å, Crystal structure of histone deacetylase 4 (HDAC4) in complex with a SMRT corepressor…

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