3ABT

Crystal Structure of LSD1 in complex with trans-2-pentafluorophenylcyclopropylamine

Summary for 3ABT

• Entry DOI: 10.2210/pdb3abt/pdb
• Related: 2dw4 2uxx 2z5u 3abu
• Descriptor: Lysine-specific histone demethylase 1, [(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]methyl (2R,3S,4S)-2,3,4-trihydroxy-5-[(1R,3R,3aS)-1-hydroxy-10,11-dimethyl-4,6-dioxo-3-(pentafluorophenyl)-2,3,5,6-tetrahydro-1H-benzo[g]pyrrolo[2,1-e]pteridin-8(4H)-yl]pentyl dihydrogen diphosphate (2 entities in total)
• Functional Keywords: amine oxidase, histone demethylase, tower domain, h3k4, structural genomics, riken structural genomics/proteomics initiative, rsgi, chromatin regulator, developmental protein, fad, nucleus, oxidoreductase, phosphoprotein, repressor, transcription, transcription regulation, nppsfa, national project on protein structural and functional analyses
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus : O60341
• Total number of polymer chains: 1
• Total formula weight: 74661.92

Authors

Mimasu, S.,Umezawa, N.,Sato, S.,Higuchi, T.,Umehara, T.,Yokoyama, S.,RIKEN Structural Genomics/Proteomics Initiative (RSGI) (deposition date: 2009-12-21, release date: 2010-07-07, Last modification date: 2023-11-01)

Primary citation

Mimasu, S.,Umezawa, N.,Sato, S.,Higuchi, T.,Umehara, T.,Yokoyama, S.
Structurally Designed trans-2-Phenylcyclopropylamine Derivatives Potently Inhibit Histone Demethylase LSD1/KDM1
Biochemistry, 49:6494-6503, 2010

PubMed Abstract: Lysine-specific demethylase 1 (LSD1/KDM1) demethylates histone H3, in addition to tumor suppressor p53 and DNA methyltransferase 1 (Dnmt1), thus regulating eukaryotic gene expression by altering chromatin structure. Specific inhibitors of LSD1 are desired as anticancer agents, because LSD1 aberrations are associated with several cancers, and LSD1 inhibition restores the expression of abnormally silenced genes in cancerous cells. In this study, we designed and synthesized several candidate compounds to inhibit LSD1, based on the structures of LSD1 and monoamine oxidase B (MAO-B), in complex with an antidepressant tranylcypromine (2-PCPA) derivative. Compound S2101 exhibited stronger LSD1 inhibition than tranylcypromine and the known small LSD1 inhibitors in LSD1 demethylation assays, with a k(inact)/K(I) value of 4560 M(-1) s(-1). In comparison with tranylcypromine, the compound displayed weaker inhibition to the monoamine oxidases. The inhibition modes of the two 2-PCPA derivatives, 2-PFPA and S1201, were identified by determination of the inhibitor-bound LSD1 structures, which revealed the enhanced stability of the inhibitor-FAD adducts by their interactions with the surrounding LSD1 residues. These molecules are potential pharmaceutical candidates for cancer or latent virus infection, as well as research tools for LSD1-related biological investigations.

PubMed: 20568732
DOI: 10.1021/bi100299r

Experimental method

X-RAY DIFFRACTION (3.2 Å)