6S35

LSD1/CoREST1 complex with macrocyclic peptide inhibitor

Summary for 6S35

• Entry DOI: 10.2210/pdb6s35/pdb
• Descriptor: Lysine-specific histone demethylase 1A, REST corepressor 1, ALA-ARG-(D)LYS-MET-GLN-GLU-ALA-ARG-LYS-SER-THR, ... (4 entities in total)
• Functional Keywords: inhibitor, complex, flavoprotein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 96818.09

Authors

Talibov, V.O.,Dobritzsch, D. (deposition date: 2019-06-24, release date: 2020-02-26, Last modification date: 2024-11-20)

Primary citation

Yang, J.,Talibov, V.O.,Peintner, S.,Rhee, C.,Poongavanam, V.,Geitmann, M.,Sebastiano, M.R.,Simon, B.,Hennig, J.,Dobritzsch, D.,Danielson, U.H.,Kihlberg, J.
Macrocyclic Peptides Uncover a Novel Binding Mode for Reversible Inhibitors of LSD1.
Acs Omega, 5:3979-3995, 2020

PubMed Abstract: Lysine-specific demethylase 1 (LSD1) is an epigenetic enzyme which regulates the methylation of Lys4 of histone 3 (H3) and is overexpressed in certain cancers. We used structures of H3 substrate analogues bound to LSD1 to design macrocyclic peptide inhibitors of LSD1. A linear, Lys4 to Met-substituted, 11-mer () was identified as the shortest peptide distinctly interacting with LSD1. It was evolved into macrocycle 31, which was >40 fold more potent ( = 2.3 μM) than . Linear and macrocyclic peptides exhibited unexpected differences in structure-activity relationships for interactions with LSD1, indicating that they bind LSD1 differently. This was confirmed by the crystal structure of in complex with LSD1-CoREST1, which revealed a novel binding mode at the outer rim of the LSD1 active site and without a direct interaction with FAD. NMR spectroscopy of suggests that macrocyclization restricts its solution ensemble to conformations that include the one in the crystalline complex. Our results provide a solid basis for the design of optimized reversible LSD1 inhibitors.

PubMed: 32149225
DOI: 10.1021/acsomega.9b03493

Experimental method

X-RAY DIFFRACTION (3.1 Å)