Drug Rescuing by Cryo-EM

[Speaker] Yoshinori Fujiyoshi:1
1:Cellular and Structural Physiology Institute (CeSPI), Nagoya University, Japan

We proposed a strategy named Drug Rescuing, as a possible solution for an effective drug development. Many lead compounds as well as target proteins have to be thrown into garbage box because of adverse effects. We will be able to rescue the target and compounds as a drug candidate by modifying the ligand chemical on the unrelated parts for pharmacologic action. Structural information of the ligand and membrane protein complex is therefore crucially important for the modification. As an example, based on electron crystallography utilizing a helium cooled cryo-EM [1], we could discriminate 8 water molecules in the water channel AQP4 [2], while their densities were blurred in the higher resolution structure by X-ray crystallography [3]. The counterintuitive notion could be attributed to the difference of surround atmosphere for structure analyses of membrane proteins. The characteristic distribution of the dielectric constants in membrane produces large dipole moment of the two short helices of water channels, whereas the dipole moment without lipid bilayer is very small. In cooperation with the electrostatic field of two short helices, the arrangement of carbonyl groups in the channel act as binding sites in the narrow channel with highly hydrophobic surfaces and lowers the energy barrier for water molecules entering such narrow water channel. These structural studies strongly suggested that electron crystallography is very powerful method for understanding physiological functions of membrane proteins as well as drug development. However, the necessity of crystallization makes this method less popular in the structural biology field. By single particle analysis, many structures have been analyzed. In very short period, we could analyze structure of gap junction channel by the method [5]. Then Drug Rescuing could be realistic method for drug development.
[1] Y Fujiyoshi, Adv. Biophys., 35, 25-80 (1998). [2] K Tani et al., J. Mol. Biol., 389, 694-706 (2009). [3] JD Ho et al., Proc. Natl. Acad. Sci. USA, 106, 7437-7442 (2009). [4] M Liao et al., Nature, 504, 107-112 (2013). [5] A Oshima et al., Nature Comms, 7, 13681 (2016).

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