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Albany 2019: 20th Conversation - Abstracts

category image Albany 2019
Conversation 20
June 11-15 2019
Adenine Press (2019)

Cryo-EM and drug discovery

Cryo-EM has transitioned rapidly in the last few years from being a method that was only capable of handling a small subset of cryo-EM worthy specimens, to one that is useful for analysis of a very large spectrum of protein complexes (Subramaniam 2019). This transition of cryo-EM from being a technology that was billed as a tool to analyze large and/or highly symmetric specimens, to one that can successfully tackle a range of proteins and protein complexes of broad general interest has been transformative. The structures of an impressive number of proteins, small and large, sometimes with extensive conformational spread, have been successfully analyzed by cryo-EM. Many of these protein complexes may never be coaxed to produce well-ordered crystals for study by X-ray crystallography. It is important to recognize that in almost every instance, these selected successes in the application of cryo-EM rest on decades of advances in biochemistry, biophysics and protein science that laid the necessary groundwork. Nor can we overlook the fact that the landscape of macromolecular entities that are still intractable to analysis by cryo-EM remains immense. Yet, the future looks bright, and there is every reason to hope that an increasingly complex array of biological assemblies will be tackled by cryo-EM.

Work in my laboratory has focused on the application of cryo-EM to small dynamic protein assemblies, with particular emphasis on its use for drug discovery and therapeutic applications, and for the development of image processing methods to improve resolution (Banerjee et al 2016, Meyerson et al 2016, Guo et al 2017, Chittori et al 2018, Kang et al 2018). In my presentation, I will discuss recent examples where we have used cryo-EM in this context to study metabolic enzyme complexes, ion channels, nucleic-acid protein complexes and intact viruses.

References

    Banerjee, S, Bartesaghi, A, Merk, A, Rao, P. Bulfer, SL, Yan, Y, Green, N, Mroczkowski, B, Neitz, RJ, Wipf, P, Falconieri, V, Deshaies, RJ, Milne, JLS, Huryn D, Arkin, M, Subramaniam S. (2016). 2.3 Å resolution cryo-EM structure of human p97 and mechanism of allosteric inhibition. Science 351, 871-875.

    Chittori, S, Hong, J, Saunders, H, Feng, H, Ghirlando, R, Kelly, AE, Bai, Y, Subramaniam, S. (2018). Structural mechanisms of centromeric chromosome recognition by the kinetochore protein CENP-N. Science 359, 339-343.

    Guo, T, Bartesaghi, A, Yang, H, Falconieri, V, Rao, P, Merk, A, Eng, ET, Raczkowski, AM, Fox, T, Earl, LA, Patel, D, Subramaniam, S. (2017). Cryo-EM Structures Reveal Mechanism and Inhibition of DNA Targeting by a CRISPR-Cas Surveillance Complex. Cell 171, 414-426.

    Kang, Y, Kuybeda, O, de Waal, PW, Mukherjee, S, Van Eps, N, Dutka, P, Zhou, XE, Bartesaghi, A, Erramilli, S, Morizumi, T, Gu, X, Yin, Y, Liu, P, Jiang, Y, Meng, X, Zhao, G, Melcher, K, Ernst, OP, Kossiakoff, AA, Subramaniam S, Xu, HE. (2018). Cryo-EM structure of human rhodopsin bound to an inhibitory G protein. Nature 558, 553-558.

Meyerson JR, Chittori S, Merk A, Rao P, Han TH, Serpe, M, Mayer ML, Subramaniam S. (2016). Structural basis of kainate subtype glutamate receptor desensitization. Nature 537, 567-571.

Subramaniam, S. (2019). The cryo-EM revolution: Fueling the next phase. IUCrJ 6, 1-2.

Sriram Subramaniam

Djavad Mowafaghian Centre for Brain Health
2215 Wesbrook Mall
University of British Columbia
Vancouver, BC V6T 1Z3, Canada

Ph: (604) 822-8621
E-mail: Sriram.Subramaniam@ubc.ca