期刊
STRUCTURE
卷 22, 期 8, 页码 1161-1172出版社
CELL PRESS
DOI: 10.1016/j.str.2014.06.009
关键词
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资金
- Industrial Macromolecular Crystallography Association through Hauptman-Woodward Medical Research Institute
- U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357]
- National Cancer Institute [Y1-CO-1020]
- National Institute of General Medical Sciences [Y1-GM-1104]
- Office of Science, Office of Basic Energy Sciences, U.S. Department of Energy [DE-AC02-05CH11231]
AMP-activated protein kinase (AMPK) is a principal metabolic regulator affecting growth and response to cellular stress. Comprised of catalytic and regulatory subunits, each present in multiple forms, AMPK is best described as a family of related enzymes. In recent years, AMPK has emerged as a desirable target for modulation of numerous diseases, yet clinical therapies remain elusive. Challenges result, in part, from an incomplete understanding of the structure and function of full-length heterotrimeric complexes. In this work, we provide the full-length structure of the widely expressed alpha 2 beta 1 gamma 1 isoform of mammalian AMPK, along with detailed kinetic and biophysical characterization. We characterize binding of the broadly studied synthetic activator A769662 and its analogs. Our studies follow on the heels of the recent disclosure of the alpha 2 beta 1 gamma 1 structure and provide insight into the distinct molecular mechanisms of AMPK regulation by AMP and A769662.
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