Document Detail


Sinefungin derivatives as inhibitors and structure probes of protein lysine methyltransferase SETD2.
MedLine Citation:
PMID:  23043551     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Epigenetic regulation is involved in numerous physiological and pathogenic processes. Among the key regulators that orchestrate epigenetic signaling are over 50 human protein lysine methyltransferases (PKMTs). Interrogation of the functions of individual PKMTs can be facilitated by target-specific PKMT inhibitors. Given the emerging need for such small molecules, we envisioned an approach to identify target-specific methyltransferase inhibitors by screening privileged small-molecule scaffolds against diverse methyltransferases. In this work, we demonstrated the feasibility of such an approach by identifying the inhibitors of SETD2. N-propyl sinefungin (Pr-SNF) was shown to interact preferentially with SETD2 by matching the distinct transition-state features of SETD2's catalytically active conformer. With Pr-SNF as a structure probe, we further revealed the dual roles of SETD2's post-SET loop in regulating substrate access through a distinct topological reconfiguration. Privileged sinefungin scaffolds are expected to have broad use as structure and chemical probes of methyltransferases.
Authors:
Weihong Zheng; Glorymar Ibáñez; Hong Wu; Gil Blum; Hong Zeng; Aiping Dong; Fengling Li; Taraneh Hajian; Abdellah Allali-Hassani; Maria F Amaya; Alena Siarheyeva; Wenyu Yu; Peter J Brown; Matthieu Schapira; Masoud Vedadi; Jinrong Min; Minkui Luo
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-10-23
Journal Detail:
Title:  Journal of the American Chemical Society     Volume:  134     ISSN:  1520-5126     ISO Abbreviation:  J. Am. Chem. Soc.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-31     Completed Date:  2013-04-01     Revised Date:  2013-11-06    
Medline Journal Info:
Nlm Unique ID:  7503056     Medline TA:  J Am Chem Soc     Country:  United States    
Other Details:
Languages:  eng     Pagination:  18004-14     Citation Subset:  IM    
Affiliation:
Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Data Bank Information
Bank Name/Acc. No.:
PDB/4FMU;  4H12
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MeSH Terms
Descriptor/Qualifier:
Adenosine / analogs & derivatives*,  chemical synthesis,  chemistry,  pharmacology
Enzyme Inhibitors / chemical synthesis,  chemistry,  pharmacology*
Histone-Lysine N-Methyltransferase / antagonists & inhibitors*,  metabolism
Humans
Models, Molecular
Molecular Probes / chemical synthesis,  chemistry,  pharmacology*
Structure-Activity Relationship
Grant Support
ID/Acronym/Agency:
1R01GM096056/GM/NIGMS NIH HHS; R01 GM096056/GM/NIGMS NIH HHS; R21 NS071520/NS/NINDS NIH HHS; R21NS071520/NS/NINDS NIH HHS; //Canadian Institutes of Health Research; //Wellcome Trust
Chemical
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Molecular Probes; 58-61-7/Adenosine; EC 2.1.1.43/Histone-Lysine N-Methyltransferase; EC 2.1.1.43/Set2 protein, human; W2U467CIIL/sinefungin
Comments/Corrections

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