Journal
BIOCONJUGATE CHEMISTRY
Volume 26, Issue 4, Pages 690-698Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.bioconjchem.5b00021
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Funding
- Platform for Drug Discovery, Informatics, and Structural Life Science
- Ministry of Education, Culture, Sports, Science and Technology, Japan [22790116, 25860090]
- MEXT
- Takeda Science Foundation, Japan
- Grants-in-Aid for Scientific Research [25860090, 22790116] Funding Source: KAKEN
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Covalent modification of proteins is important for normal cellular regulation. Here, we report on the covalent modification of peroxisome proliferator-activated receptor gamma (PPAR gamma), an important drug target, by oxo-fatty acids. In this study, ESI mass spectroscopy showed that the reactivities of oxo-fatty acids with PPAR gamma are different from one another and that these behaviors are related to the structure of the fatty acids. X-ray crystallography showed that three oxo-fatty acids all bound to the same residue of PPAR? (Cys285), but displayed different hydrogen bonding modes. Moreover, fatty acids formed covalent bonds with both PPAR? moieties in the homodimer, one in an active conformation and the other in an alternative conformation. These two conformations may explain why covalently bound fatty acids show partial rather than full agonist activity.
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