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ARS Home » Pacific West Area » Albany, California » Western Regional Research Center » Healthy Processed Foods Research » Research » Publications at this Location » Publication #375981
Research Project: Defining, Measuring, and Mitigating Attributes that Adversely Impact the Quality and Marketability of Foods

Location: Healthy Processed Foods Research

Title: Atomic-resolution structures of type I ribosome inactivating protein alpha-momorharin with different substrate analogs

Author
item FAN, XIAOJIAO - University Of Science And Technology Of China
item WANG, YANG - Illinois Institute Of Technology
item GUO, FENG - Illinois Institute Of Technology
item Zhang, Yuzhu
item JIN, TENGCHUAN - University Of Science And Technology Of China

Submitted to: International Journal of Biological Macromolecules
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/3/2020
Publication Date: 7/10/2020
Citation: Fan, X., Wang, Y., Guo, F., Zhang, Y., Jin, T. 2020. Atomic-resolution structures of type I ribosome inactivating protein alpha-momorharin with different substrate analogs. International Journal of Biological Macromolecules. 164:265-276. https://doi.org/10.1016/j.ijbiomac.2020.07.063.
DOI: https://doi.org/10.1016/j.ijbiomac.2020.07.063

Interpretive Summary: Alpha-momorcharin (alpha-MMC) is a type I Ribosome inactivating protein (RIP) isolated from the seed of bitter melon. It is a prototype RIP protein that has been extensively studied. It is known that transgenic rice harboring the alpha-MMC gene obtained enhanced resistance to blast fungus and that alpha-MMC increased the defense response of tobacco plants to a variety of plant viruses. When conjugated with antibodies or cell-penetrating peptides, RIPs were also used in medical applications to kill tumors or invected cells. However, RIP toxins can also be used as biological weapons to cause widespread food poisoning. Thus, it is vital to develop vaccines and inhibitors to treat RIP poisoning. To date, only ricin vaccines (RiVax™ and RVEc™) have been developed to prevent a possible biological poison attack. Therefore, more detailed structural information of alpha-MMC with different substrate analogs are needed to provide insights into its enzymatic mechanisms and to enable the engineering of its variants for developing vaccines and potential drugs. In this study, different substrate analogs of alpha-MMC from bitter melon were crystallized with the enzyme, and structures of the complexes are described. The results showed, for the first time, that not only adenine but also guanine and their analogs can effectively bind to alpha-MMC. The information obtained will enable the development of new toxin inhibitors. It may also facilitate the development of alpha-MMC based medicine to improve the treatment of solid tumor and virus infection.

Technical Abstract: Alpha-momorcharin (Alpha-MMC) from the seed of bitter melon is a type I ribosome inactivating protein that removes a specific adenine from 28S rRNA and inhibits protein biosynthesis. Here, we report seven crystal complex structures of alpha-MMC with different substrate analogs (adenine, AMP, cAMP, dAMP, ADP, GMP, and xanthosine) at 1.08 Å to 1.52 Å resolution. These structures reveal that not only adenine, but also guanine and their analogs can effectively bind to alpha-MMC. The side chain of Tyr93 adopts two conformations, serving as a switch to open and close the substrate binding pocket of alpha-MMC. Although adenine, AMP, GMP, and guanine are located in a similar active site in different RIPs, residues involved in the interaction between RIPs and substrate analogs are slightly different. Complex structures of alpha-MMC with different substrate analogs solved in this study provide useful information on its enzymatic mechanisms and may enable the development of new inhibitors to treat the poisoning of alpha-MMC.