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2013 Scientific Report

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VARI |

VARI | 2013 Research Interests The Laboratory of Structural Biology and Biochemistry studies the structure and function of proteins that have central roles in cellular signaling. To do so, we employ X-ray crystallography in combination with biochemical and cellular methods to identify structural mechanisms of signaling at high resolution. In addition to their fundamental physiological roles, most signaling proteins are also important targets of therapeutic drugs. Determination of the three-dimensional structures of protein–drug complexes at atomic resolution allows a detailed understanding of how a drug binds its target and modifies its activity. This knowledge allows the rational design of new and better drugs against diseases such as diabetes, cancer, and neurological disorders. Two areas of focus in the lab are the adenosine-monophosphate (AMP)-activated protein kinase (AMPK), a cellular energy and nutrient sensor, and the receptors and key signaling proteins for a plant hormone, abscisic acid (ABA). AMP-activated protein kinase Cells use ATP to drive energy-consuming cellular processes such as muscle contraction, cell growth, and neuronal excitation. AMPK is a three-subunit protein kinase that functions as a sensor of the energy status in human cells. Its kinase activity is triggered by energy stress (i.e., a drop in the ratio of ATP to AMP/ADP), activating ATP-generating pathways and reducing energy-consuming programs. To adjust energy balance, AMPK regulates • Almost all cellular metabolic processes (activation of ATP-generating pathways such as glucose and fatty acid uptake and catabolism, and inhibition of energy-consuming pathways such as the synthesis of glycogen, fatty acids, cholesterol, proteins, and ribosomal RNA) • Whole-body energy balance (appetite regulation in the hypothalamus via leptin, adiponectin, ghrelin, and cannabinoids) • Many nonmetabolic processes (cell growth and proliferation, mitochondrial homeostasis, autophagy, aging, neuronal activity, and cell polarity). Due to its central roles in the uptake and metabolism of glucose and fatty acids, AMPK is an important pharmacological target for the treatment of diabetes and obesity. Moreover, AMPK activation restrains the growth and metabolism of tumor cells and has thus become an exciting new target for cancer therapy. In this project we strive to determine the structural mechanisms of AMPK regulation by direct binding of AMP, ADP, ATP, drugs, and glycogen, in order to provide a structural framework for the rational design of new therapeutic AMPK modulators. 39

Van Andel Research Institute | Scientific Report Abscisic acid Abscisic acid is an ancient signaling molecule that is found in plants, fungi, and metazoans ranging from sponges to humans. In plants, ABA is an essential hormone and is also the central regulator protecting plants against abiotic stresses such as drought, cold, and high salinity. These stresses—most prominently, the scarcity of fresh water—are major limiting factors in crop production and therefore major contributors to malnutrition. Malnutrition affects an estimated one billion people and contributes to more than 50% of human disease worldwide, including cancer and infectious diseases. We have determined the structure of ABA receptors in the free state and bound to ABA. Using computational receptor docking experiments, we have identified and verified synthetic small-molecule receptor activators as new chemical scaffolds toward the development of new, environmentally friendly, and affordable compounds that will protect plants against abiotic stresses. We have also identified the structural mechanism of the core ABA signaling pathway, which will allow modulation of this pathway through genetic engineering of crop plants. Recent Publications Pal, Kuntal, Karsten Melcher, and H. Eric Xu. 2012. Structure and mechanism for recognition of peptide hormones by Class B G-protein-coupled receptors. Acta Pharmacologica Sinica 33(3): 300–311. Soon, Fen-Fen, Ley-Moy Ng, X. Edward Zhou, Graham M. West, Amanda Kovach, M. H. Eileen Tan, Kelly M. Suino-Powell, Yuanzheng He, Yong Xu, Michael J. Chalmers, et al. 2012. Molecular mimicry regulates ABA signaling by SnRK2 kinases and PP2C phosphatases. Science 335(6064): 85–88. Soon, Fen-Fen, Kelly M. Suino-Powell, Jun Li, Eu-Leong Yong, H. Eric Xu, and Karsten Melcher. 2012. Abscisic acid signaling: thermal stability shift assays as tool to analyze hormone perception and signal transduction. PLoS One 7(10): e47857. Zhou, X. Edward, Karsten Melcher, and H. Eric Xu. 2012. Structure and activation of rhodopsin. Acta Pharmacologica Sinica 33(3): 291–299. Zhou, X. Edward, Fen-Fen Soon, Ley-Moy Ng, Amanda Kovach, Kelly M. Suino-Powell, Jun Li, Eu-Leong Yong, Jian-Kang Zhu, H. Eric Xu, and Karsten Melcher. 2012. Catalytic mechanism and kinase interactions of ABA-signaling PP2C phosphatases. Plant Signaling & Behavior 7(5): 581–588. Ng, Ley-Moy, Fen-Fen Soon, X. Edward Zhou, Graham M. West, Amanda Kovach, Kelly M. Suino-Powell, Michael J. Chalmers, Jun Li, Eu-Leong Yong, Jian-Kang Zhu, et al. 2011. Structural basis for basal activity and autoactivation of abscisic acid (ABA) signaling SnRK2 kinases. Proceedings of the National Academy of Sciences U.S.A. 108(52): 21259–21264. Zhi, Xiaoyong, X. Edward Zhou, Karsten Melcher, Daniel L. Motola, Verena Gelmedin, John Hawdon, Steven A. Kliewer, David J. Mangelsdorf, and H. Eric Xu. 2011. Structural conservation of ligand binding reveals a bile acid–like signaling pathway in nematodes. Journal of Biological Chemistry 287(7): 4894–4903. 40

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