5A2S: Histone deacetylase 4

Potent, selective and CNS-penetrant tetrasubstituted cyclopropane class IIa histone deacetylase (HDAC) inhibitors. Determined by X-ray diffraction at 2.65 Å resolution. Released 10 Feb 2016.

Method: X-ray diffraction
Resolution: 2.65 Å
Organism: HOMO SAPIENS
Chains: 2
Atoms: 5,783
Mol. weight: 86.55 kDa
Ligands: ZN, OTF
Released: 10 Feb 2016

Explore 5A2S in 3D Show helices and sheets RCSB PDB PDBe

Secondary structure: helices and β-sheets

5A2S contains 50 α-helices and 30 β-strands across 2 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: 27 helices, 15 β-strands

Element	Residues	Length	Sheet
β-strand	654-657	4	1
α-helix	660-664	5
α-helix	672-674	3
α-helix	680-691	12
α-helix	695-697	3
β-strand	699-701	3	1
α-helix	702-703	2
α-helix	705-707	3
α-helix	708-711	4
α-helix	717-724	8
α-helix	727-733	7
α-helix	742-744	3
β-strand	747-748	2	2
β-strand	754-755	2	2
β-strand	761	1	2
α-helix	767-786	20
β-strand	792-795	4	1
β-strand	810	1	3
β-strand	813	1	3
α-helix	817-829	13
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	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	948	1	4
α-helix	952-960	9
α-helix	964-966	3
β-strand	968-972	5	1
α-helix	978-992	15
α-helix	995-1001	7
α-helix	1002-1006	5
α-helix	1007-1010	4
α-helix	1011-1023	13
α-helix	1024-1026	3
α-helix	1029-1031	3

Chain B: 23 helices, 15 β-strands

Element	Residues	Length	Sheet
β-strand	655-657	3	5
α-helix	660-664	5
α-helix	680-690	11
α-helix	695-697	3
β-strand	699-700	2	5
α-helix	705-707	3
α-helix	708-711	4
α-helix	717-722	6
α-helix	727-733	7
β-strand	747-748	2	6
β-strand	754-755	2	6
β-strand	761	1	6
α-helix	767-786	20
β-strand	793-795	3	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	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	978-992	15
α-helix	995-1001	7
α-helix	1002-1005	4
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	protein	395	HOMO SAPIENS	P56524 (AlphaFold model)

Sequence of entity 1 (A, B), FASTA

>5A2S_1 HISTONE DEACETYLASE 4 (chains A, B)
MGSTKPRFTTGLVYDTLMLKHQCTCGSSSSHPEHAGRIQSIWSRLQETGLRGKCECIRGR
KATLEELQTVHSEAHTLLYGTNPANRQKLDSKKLLGSLASVFVRLPCGGVGVDSDTIWNE
VHSAGAARLAVGCVVELVFKVATGELKNGFAVVRPPGHHAEESTPMGFCYFNSVAVAAKL
LQQRLSVSKILIVDWDVHHGNGTQQAFYSDPSVLYMSLHRYDDGNFFPGSGAPDEVGTGP
GVGFNVNMAFTGGLDPPMGDAEYLAAFRTVVMPIASEFAPDVVLVSSGFDAVEGHPTPLG
GYNLSARCFGYLTKQLMGLAGGRIVLALEGGHDLTAICDASEACVSALLGNELDPLPEKV
LQQRPNANAVRSMEKVMEIHSKYWRCLQRHHHHHH

Ligands and cofactors

ID	Name	Formula	Copies
ZN	Zinc ion	Zn	4
OTF	(1S,2S,3S)-1-fluoranyl-2-[4-(5-fluoranylpyrimidin-2-yl)phenyl]-N-oxidanyl-3-phe…	C20 H15 F2 N3 O2	2

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

Primary citation

Potent, Selective, and Cns-Penetrant Tetrasubstituted Cyclopropane Class Iia Histone Deacetylase (Hdac) Inhibitors. Luckhurst, C.A., Breccia, P., Stott, A.J. et al. ACS Med Chem Lett (2016) 7:34. DOI 10.1021/ACSMEDCHEMLETT.5B00302 · 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…
6FYZ 2.15 Å, Development and characterization of a CNS-penetrant benzhydryl hydroxamic acid class IIa…
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
5ZOP 2.7 Å, Crystal structure of histone deacetylase 4 (HDAC4) in complex with a SMRT corepressor…

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