5LBQ

LSD1-CoREST1 in complex with quinazoline-derivative reversible inhibitor

Summary for 5LBQ

• Entry DOI: 10.2210/pdb5lbq/pdb
• Descriptor: Lysine-specific histone demethylase 1A, REST corepressor 1, FLAVIN-ADENINE DINUCLEOTIDE, ... (4 entities in total)
• Functional Keywords: oxidoreductase-repressor complex, lsd1, kdm1a, corest1, chromatin, epigenetic, oxidoreductase/repressor
• Biological source: Homo sapiens (Human); More
• Cellular location: Nucleus : O60341 Q9UKL0
• Total number of polymer chains: 2
• Total formula weight: 103310.10

Authors

Speranzini, V.,Rotili, D.,Ciossani, G.,Pilotto, S.,Forgione, M.,Lucidi, A.,Forneris, F.,Velankar, S.,Mai, A.,Mattevi, A. (deposition date: 2016-06-16, release date: 2016-09-21, Last modification date: 2024-01-10)

Primary citation

Speranzini, V.,Rotili, D.,Ciossani, G.,Pilotto, S.,Marrocco, B.,Forgione, M.,Lucidi, A.,Forneris, F.,Mehdipour, P.,Velankar, S.,Mai, A.,Mattevi, A.
Polymyxins and quinazolines are LSD1/KDM1A inhibitors with unusual structural features.
Sci Adv, 2:e1601017-e1601017, 2016

PubMed Abstract: Because of its involvement in the progression of several malignant tumors, the histone lysine-specific demethylase 1 (LSD1) has become a prominent drug target in modern medicinal chemistry research. We report on the discovery of two classes of noncovalent inhibitors displaying unique structural features. The antibiotics polymyxins bind at the entrance of the substrate cleft, where their highly charged cyclic moiety interacts with a cluster of positively charged amino acids. The same site is occupied by quinazoline-based compounds, which were found to inhibit the enzyme through a most peculiar mode because they form a pile of five to seven molecules that obstruct access to the active center. These data significantly indicate unpredictable strategies for the development of epigenetic inhibitors.

PubMed: 27626075
DOI: 10.1126/sciadv.1601017

Experimental method

X-RAY DIFFRACTION (3.3 Å)