Macrocyclic Peptides Uncover a Novel Binding Mode for Reversible Inhibitors of LSD1

Peintner, Stefan, 1991- (author): Uppsala universitet,Organisk kemi,Uppsala Univ, Dept Chem BMC, SE-75123 Uppsala, Sweden

Simon, Bernd (author): EMBL Heidelberg, Struct & Computat Biol Unit, D-69117 Heidelberg, Germany

Hennig, Janosch (author): EMBL Heidelberg, Struct & Computat Biol Unit, D-69117 Heidelberg, Germany

Danielson, U. Helena, Professor, 1959- (author): Uppsala universitet,Biokemi,Science for Life Laboratory, SciLifeLab

(creator_code:org_t)

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Abstract Subject headings

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 (4) was identified as the shortest peptide distinctly interacting with LSD1. It was evolved into macrocycle 31, which was >40 fold more potent K-i = 2.3 mu M) than 4. 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 31 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 31 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.

By the author/editor: Yang, Jie; Talibov, Vladimi ...; Peintner, Stefan ...; Rhee, Claire; Poongavanam, Vas ...; Geitmann, Matthi ...; show more...; Sebastiano, Matt ...; Simon, Bernd; Hennig, Janosch; Dobritzsch, Dore ...; Danielson, U. He ...; Kihlberg, Jan; show less...

About the subject

NATURAL SCIENCES: NATURAL SCIENCES; and Biological Scien ...; and Biochemistry and ...

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