Protein recognition by short peptide reversible inhibitors of the chromatin-modifying LSD1/CoREST lysine demethylase
Protein recognition by short peptide reversible inhibitors of the chromatin-modifying LSD1/CoREST lysine demethylase
The combinatorial assembly of protein complexes is at the heart of chromatin biology. Lysine demethylase LSD1(KDM1A)/CoREST beautifully exemplifies this concept. The active site of the enzyme tightly associates to the N-terminal domain of transcription factors of the SNAIL1 family, which therefore can competitively inhibit the binding of the N-terminal tail of the histone substrate. Our enzymatic, crystallographic, spectroscopic, and computational studies reveal that LSD1/CoREST can bind to a hexapeptide derived from the SNAIL sequence through recognition of a positively charged ?-helical turn that forms upon binding to the enzyme. Variations in sequence and length of this six amino acid ligand modulate affinities enabling the same binding site to differentially interact with proteins that exert distinct biological functions. The discovered short peptide inhibitors exhibit antiproliferative activities and lay the foundation for the development of peptidomimetic small molecule inhibitors of LSD1.
1677-1682
Tortorici, Marcello
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Borrello, Maria Teresa
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Tardugno, Maria
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Chiarelli, Laurent R.
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Pilotto, Simona
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Ciossani, Giuseppe
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Vellore, Nadeem A.
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Bailey, Sarah G.
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Cowan, Jonathan
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O'Connell, Maria
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Crabb, Simon J.
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Packham, Graham
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Mai, Antonello
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Baron, Riccardo
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Ganesan, A.
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Mattevi, Andrea
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16 August 2013
Tortorici, Marcello
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Borrello, Maria Teresa
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Tardugno, Maria
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Chiarelli, Laurent R.
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Pilotto, Simona
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Ciossani, Giuseppe
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Vellore, Nadeem A.
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Bailey, Sarah G.
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Cowan, Jonathan
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O'Connell, Maria
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Crabb, Simon J.
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Packham, Graham
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Mai, Antonello
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Baron, Riccardo
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Ganesan, A.
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Mattevi, Andrea
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Tortorici, Marcello, Borrello, Maria Teresa, Tardugno, Maria, Chiarelli, Laurent R., Pilotto, Simona, Ciossani, Giuseppe, Vellore, Nadeem A., Bailey, Sarah G., Cowan, Jonathan, O'Connell, Maria, Crabb, Simon J., Packham, Graham, Mai, Antonello, Baron, Riccardo, Ganesan, A. and Mattevi, Andrea
(2013)
Protein recognition by short peptide reversible inhibitors of the chromatin-modifying LSD1/CoREST lysine demethylase.
ACS Chemical Biology, 8 (8), .
(doi:10.1021/cb4001926).
(PMID:23721412)
Abstract
The combinatorial assembly of protein complexes is at the heart of chromatin biology. Lysine demethylase LSD1(KDM1A)/CoREST beautifully exemplifies this concept. The active site of the enzyme tightly associates to the N-terminal domain of transcription factors of the SNAIL1 family, which therefore can competitively inhibit the binding of the N-terminal tail of the histone substrate. Our enzymatic, crystallographic, spectroscopic, and computational studies reveal that LSD1/CoREST can bind to a hexapeptide derived from the SNAIL sequence through recognition of a positively charged ?-helical turn that forms upon binding to the enzyme. Variations in sequence and length of this six amino acid ligand modulate affinities enabling the same binding site to differentially interact with proteins that exert distinct biological functions. The discovered short peptide inhibitors exhibit antiproliferative activities and lay the foundation for the development of peptidomimetic small molecule inhibitors of LSD1.
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Accepted/In Press date: 30 May 2013
e-pub ahead of print date: 30 May 2013
Published date: 16 August 2013
Organisations:
Cancer Sciences
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Local EPrints ID: 365799
URI: http://eprints.soton.ac.uk/id/eprint/365799
ISSN: 1554-8929
PURE UUID: c2f6c896-a7ca-4d78-bfb7-27b4e9f79c62
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Date deposited: 17 Jun 2014 09:20
Last modified: 15 Mar 2024 03:16
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Contributors
Author:
Marcello Tortorici
Author:
Maria Teresa Borrello
Author:
Maria Tardugno
Author:
Laurent R. Chiarelli
Author:
Simona Pilotto
Author:
Giuseppe Ciossani
Author:
Nadeem A. Vellore
Author:
Sarah G. Bailey
Author:
Jonathan Cowan
Author:
Maria O'Connell
Author:
Antonello Mai
Author:
Riccardo Baron
Author:
A. Ganesan
Author:
Andrea Mattevi
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