7ZZR

HDAC2 in complex with inhibitory ligand

Summary for 7ZZR

• Entry DOI: 10.2210/pdb7zzr/pdb
• Descriptor: Histone deacetylase 2, ZINC ION, CALCIUM ION, ... (10 entities in total)
• Functional Keywords: chromatin binding, transcription regulation, protein de-acetylation, transcription
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 3
• Total formula weight: 172240.96

Authors

Cleasby, A.,Tisi, D. (deposition date: 2022-05-26, release date: 2022-09-21, Last modification date: 2024-06-19)

Primary citation

Tamanini, E.,Miyamura, S.,Buck, I.M.,Cons, B.D.,Dawson, L.,East, C.,Futamura, T.,Goto, S.,Griffiths-Jones, C.,Hashimoto, T.,Heightman, T.D.,Ishikawa, S.,Ito, H.,Kaneko, Y.,Kawato, T.,Kondo, K.,Kurihara, N.,McCarthy, J.M.,Mori, Y.,Nagase, T.,Nakaishi, Y.,Reeks, J.,Sato, A.,Schopf, P.,Tai, K.,Tamai, T.,Tisi, D.,Woolford, A.J.
Fragment-Based Discovery of a Novel, Brain Penetrant, Orally Active HDAC2 Inhibitor.
Acs Med.Chem.Lett., 13:1591-1597, 2022

PubMed Abstract: Fragment-based ligand discovery was successfully applied to histone deacetylase HDAC2. In addition to the anticipated hydroxamic acid- and benzamide-based fragment screening hits, a low affinity (∼1 mM) α-amino-amide zinc binding fragment was identified, as well as fragments binding to other regions of the catalytic site. This alternative zinc-binding fragment was further optimized, guided by the structural information from protein-ligand complex X-ray structures, into a sub-μM, brain penetrant, HDAC2 inhibitor () capable of modulating histone acetylation levels .

PubMed: 36262388
DOI: 10.1021/acsmedchemlett.2c00272

Experimental method

X-RAY DIFFRACTION (2.168 Å)