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2015 Scientific Report

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Van Andel Research

Van Andel Research Institute | Scientific Report 2015 We have determined the structure of ABA receptors in their free state and while bound to ABA. Using computational receptordocking 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. Folate receptors Folates (folic acid and derivatives) are one-carbon donors required for the synthesis of DNA. Rapidly dividing cells, such as cancer cells, require rapid DNA synthesis and are therefore selectively dependent on high folate levels. This vulnerability has been therapeutically exploited since the 1940s, when toxic folate analogs (antifolates) were used as the first chemotherapeutic agents. However, current antifolates have severe side effects such as immunosuppression, nausea, and hair loss, because they also kill nonmalignant proliferative cells. Cells can take up folates in two main ways: by a ubiquitous, high-capacity, low-affinity uptake system known as RFC and by folate receptors, which are cysteine-rich cell surface glycoproteins that allow high-affinity uptake of folates by endocytosis but that do not take up the current antifolate drugs. While folate receptors are expressed at very low levels in most tissues, they are “hijacked” and expressed at high levels in numerous cancers. This selective expression has been therapeutically and diagnostically exploited by the administration of antibodies against folate receptor , of folate-based imaging agents, and of folate-conjugated drugs and toxins. We expect that targeting antifolates for uptake by folate receptors, but not by the RFC, would greatly reduce the side effects of antifolate chemotherapy. We have determined the structure of folate receptor in complex with folic acid. The structure, validated by systematic mutations of pocket residues and quantitative folic acid binding assays, has provided a detailed map of the extensive interactions between folic acid and FR. It also provides a structural framework for the design of novel antifolates that are selectively taken up by folate receptors. Our short-term goal is to determine the structures of novel, preclinical chemotherapeutic antifolates, bound to folate receptors and bound to the folate-metabolizing enzymes they inhibit, in order to rationally design novel antifolates that selectively target cancer cells. Recent Publications Li, Xiaodan, Lili Wang, Edward X. Zhou, Jiyuan Ke, Parker W. de Waal, Xin Gu, M.H. Eileen Tan, Dongye Wang, Donghai Wu, et al. In press. Structural basis of AMPK regulation by adenine nucleotides and glycogen. Cell Research. He, Yuanzheng, Wei Yi, Kelly Suino-Powell, X. Edward Zhou, W. David Tolbert, Xiaobo Tang, Jing Yang, Huaiyu Yang, Jingjing Shi, et al. 2014. Structures and mechanism for the design of highly potent glucocorticoids. Cell Research 24(6): 713–726. Ng, Ley Moy, Karsten Melcher, Bin Tean Teh, and H. Eric Xu. 2014. Abscisic acid perception and signaling: structural mechanisms and applications. Acta Pharmacologica Sinica 35(5): 567–584. Zhi, Xiaoyong, X. Edward Zhou, Yuanzheng He, Christoph Zechner, Kelly M. Suino-Powell, Steven A. Kliewer, Karsten Melcher, David J. Mangelsdorf, and H. Eric Xu. 2014. Structural insights into gene repression by the orphan nuclear receptor SHP. Proceedings of the National Academy of Sciences U.S.A. 111(2): 839–844. 24

Cindy K. Miranti, Ph.D. Laboratory of Integrin Signaling and Tumorigenesis Dr. Miranti received her M.S. in microbiology from Colorado State University and her Ph.D. in biochemistry from Harvard Medical School. She was a postdoctoral fellow in the laboratory of Joan Brugge at ARIAD Pharmaceuticals, Cambridge, Massachusetts, and in the Department of Cell Biology at Harvard Medical School. Dr. Miranti joined VARI in January 2000, where she is currently an Associate Professor. She is also an Adjunct Professor in the Department of Physiology at Michigan State University. From left: Bergsma, Frank, Nollet, Schulz, Ganguly, Berger, Miranti, Jensen Staff Penny Berger, B.S. Sourik Ganguly, Ph.D. Veronique Schulz, B.S. Students Alexis Bergsma, B.S. Sander Frank, B.A. Corbin Jensen Eric Nollet, B.S. Khristal Thomas McLane Watson Jelani Zarif, M.S 25

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