Chemical synthesis of the ATAD2 bromodomain Journal Article

   


Authors: Creech, G. S.; Paresi, C.; Li, Y. M.; Danishefsky, S. J.
Article Title: Chemical synthesis of the ATAD2 bromodomain
Abstract: Due to the emerging importance of the bromodomain binding region in the study of epigenetic effectors and the vast implications for a wide variety of human disease, the bromodomain region of human ATPase family AAA+ (ATPases associated with diverse cellular activities) domain-containing protein 2 (ATAD2) was targeted for chemical synthesis. The ATAD2 bromodomain (130 aa) was divided into five strategic fragments to be assembled using native chemical ligation with a focus on maximal convergency and efficiency. The fragments were assembled with one cysteine and three thioleucine ligations, unveiling the native alanine and leucine amino acids at the ligation points following metal-free dethiylation. Synthetic highlights of the study are a photolabile dimethoxynitrobenzyl-protected glutamic acid side chain used to impede hydrolysis of the C-terminal Glu-thioester, a thiazolidine-protected thioleucine, and an efficient assembly of three fragments in a single reaction vessel with dual-mode kinetic-standard chemical ligation. With a focus on material throughput and convergency, the five peptide fragments were assembled into the native ATAD2 bromodomain region with a total of three HPLC events in 8% overall yield from the fragments.
Keywords: unclassified drug; protein domain; protein; protein binding; protein synthesis; alanine; protein secondary structure; cross reaction; mass fragmentography; leucine; hydrolysis; desulfurization; peptide synthesis; native chemical ligation; valine; proline; chemical modification; reversed phase high performance liquid chromatography; bromodomain; solid-phase peptide synthesis; priority journal; article; peptide retrosynthesis; atad2 protein
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 111
Issue: 8
ISSN: 0027-8424
Publisher: National Academy of Sciences  
Date Published: 2014-02-25
Start Page: 2891
End Page: 2896
Language: English
DOI: 10.1073/pnas.1400556111
PROVIDER: scopus
PMCID: PMC3939912
PUBMED: 24516155
DOI/URL:

http://www.scopus.com/inward/record.url?eid=2-s2.0-84896844924&partnerID=40&md5=444ad1aad307776faac3a9832c0661a3
Notes: Export Date: 2 April 2014 -- CODEN: PNASA -- Source: Scopus
Altmetric
What is Altmetric?
Citation Impact
What is Dimensions Citation Badge?
BMJ Impact Analytics
MSK Authors
  1. Samuel J Danishefsky
    539 Danishefsky
  2. Yueming Li
    132 Li
  3. Gardner Silas Creech
    2 Creech
  4. Chelsea Jordan Paresi
    3 Paresi
Related MSK Work