Abstract
Histone demethylase LSD1 regulates transcription by demethylating Lys 4 of histone H3. The crystal structure of the enzyme in complex with CoREST and a substrate-like peptide inhibitor highlights an intricate network of interactions and a folded conformation of the bound peptide. The core of the peptide structure is formed by Arg2, Gln5, and Ser 10, which are engaged in specific intramolecular H-bonds. Several charged side chains on the surface of the substrate-binding pocket establish electrostatic interactions with the peptide. The three-dimensional structure predicts that methylated Lys4 binds in a solvent inaccessible position in front of the flavin cofactor. This geometry is fully consistent with the demethylation reaction being catalyzed through a flavin-mediated oxidation of the substrate amino-methyl group. These features dictate the exquisite substrate specificity of LSD1 and provide a structural framework to explain the fine tuning of its catalytic activity and the active role of CoREST in substrate recognition.
| Original language | English |
|---|---|
| Pages (from-to) | 20070-20074 |
| Number of pages | 5 |
| Journal | Journal of Biological Chemistry |
| Volume | 282 |
| Issue number | 28 |
| DOIs | |
| Publication status | Published - Jul 13 2007 |
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ASJC Scopus subject areas
- Biochemistry
Cite this
Structural basis of LSD1-CoREST selectivity in histone H3 recognition. / Forneris, Federico; Binda, Claudia; Adamo, Antonio; Battaglioli, Elena; Mattevi, Andrea.
In: Journal of Biological Chemistry, Vol. 282, No. 28, 13.07.2007, p. 20070-20074.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Structural basis of LSD1-CoREST selectivity in histone H3 recognition
AU - Forneris, Federico
AU - Binda, Claudia
AU - Adamo, Antonio
AU - Battaglioli, Elena
AU - Mattevi, Andrea
PY - 2007/7/13
Y1 - 2007/7/13
N2 - Histone demethylase LSD1 regulates transcription by demethylating Lys 4 of histone H3. The crystal structure of the enzyme in complex with CoREST and a substrate-like peptide inhibitor highlights an intricate network of interactions and a folded conformation of the bound peptide. The core of the peptide structure is formed by Arg2, Gln5, and Ser 10, which are engaged in specific intramolecular H-bonds. Several charged side chains on the surface of the substrate-binding pocket establish electrostatic interactions with the peptide. The three-dimensional structure predicts that methylated Lys4 binds in a solvent inaccessible position in front of the flavin cofactor. This geometry is fully consistent with the demethylation reaction being catalyzed through a flavin-mediated oxidation of the substrate amino-methyl group. These features dictate the exquisite substrate specificity of LSD1 and provide a structural framework to explain the fine tuning of its catalytic activity and the active role of CoREST in substrate recognition.
AB - Histone demethylase LSD1 regulates transcription by demethylating Lys 4 of histone H3. The crystal structure of the enzyme in complex with CoREST and a substrate-like peptide inhibitor highlights an intricate network of interactions and a folded conformation of the bound peptide. The core of the peptide structure is formed by Arg2, Gln5, and Ser 10, which are engaged in specific intramolecular H-bonds. Several charged side chains on the surface of the substrate-binding pocket establish electrostatic interactions with the peptide. The three-dimensional structure predicts that methylated Lys4 binds in a solvent inaccessible position in front of the flavin cofactor. This geometry is fully consistent with the demethylation reaction being catalyzed through a flavin-mediated oxidation of the substrate amino-methyl group. These features dictate the exquisite substrate specificity of LSD1 and provide a structural framework to explain the fine tuning of its catalytic activity and the active role of CoREST in substrate recognition.
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UR - http://www.scopus.com/inward/citedby.url?scp=34547132094&partnerID=8YFLogxK
U2 - 10.1074/jbc.C700100200
DO - 10.1074/jbc.C700100200
M3 - Article
C2 - 17537733
AN - SCOPUS:34547132094
VL - 282
SP - 20070
EP - 20074
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 28
ER -