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2015 Scientific Report

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Van Andel Research

Van Andel Research Institute | Scientific Report 2015 Karsten Melcher, Ph.D. Laboratory of Structural Biology and Biochemistry Dr. Melcher earned his master’s degree in biology and his Ph.D. degree in biochemistry from the Eberhard Karls Universität in Tübingen, Germany, after which he was a postdoctoral fellow at the University of Texas Southwestern Medical Center in Dallas. He was then an independent investigator at the University of Ulster in Coleraine, U.K., and at Goethe University in Frankfurt. Dr. Melcher was recruited to VARI in 2007, serving as a Research Scientist within the Laboratory of Structural Sciences. In 2011, he became Assistant Professor and Head of the Laboratory of Structural Biology and Biochemistry, and in 2013 he was promoted to Associate Professor. From left: Gu, Wang, Sridharamurthy, Li, Kovach, de Waal, Melcher, Grant Staff Parker de Waal, B.S. Stephanie Grant, B.S. Xin Gu, M.Sc. Amanda Kovach, B.S. Xiaoyin (Edward) Zhou, Ph.D. Students Mark Farha Xiaodan Li, B.S. Kelvin Searose-Xu Madhuri Sridharamurthy, B.S. Adam Thelen Lili Wang, B.S. 22

Melcher 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 cancer, diabetes, and neurological disorders. Three areas of focus in the lab are the adenosine monophosphate (AMP)–activated protein kinase (AMPK); the receptors and key signaling proteins for a plant hormone, abscisic acid (ABA); and the folate receptors. AMP-activated protein kinase (AMPK) 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 an energy sensor and regulator of homeostasis 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 metabolic pathways and cell proliferation. 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) Because of its central roles in the uptake and metabolism of glucose and fatty acids, AMPK is an important pharmacological target for treating 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. Abscisic acid Abscisic acid is an ancient signaling molecule 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. 23

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