Recently, from the Paul Schell Institute in Switzerlandbas**raj khanppn**arPh.D., University of Sydneyrachel a. northPh.D., Autonomous University of Barcelonasalvador venturaProfessor and Fudan UniversityXu YanhuiProfessors are united intrends in biochemical sciencesThe magazine ** published a publication entitled:advance, challenges, and opportunities in structural biologyReview of **,The current situation and future development trend of structural biology are summarized and prospected.
Cryo-electron microscopy (cryo-EM) technology has been developed for decades, and the endless software and hardware innovations have brought about a "resolution revolution" that has given us a deeper understanding of the structure and function of protein molecules that are closely related to life activities. Dr. Khanppn**ar and Dr. North jointly notedAt present, the cryo-EM structural analysis technology is relatively mature and reliable, however, the cryo-EM density map usually shows a large difference in local resolution, so there is a certain subjectivity in the construction and analysis of the structural model。In addition, considering the inherent limitations of different structural biology research methods, a variety of technical means should be integrated to interpret the structure-function relationship of biological macromolecules in an all-round and refined manner. Dr. Khanppn**ar proposed that the important directions for the future development of structural biology are:Artificial intelligence (AI) is combined with existing structural biology methods to understand the unknown functions of biological macromolecules.
*From Prof. CellpressVentura proposed that the study of the structure of amyloid protein associated with human neurodegenerative diseases has expanded our understanding of its molecular morphology and pathogenic mechanism. The current problem is,Single-particle cryo-EM structural studies of amyloid purified in vitro do not fully represent the true molecular configuration in vivo。The study of amyloid on native tissues using cryo-electron tomography (cryo-ET) can compensate for this limitation and maximize its native conformation. However, compared with cryo-EM single particle analysis, Cryo-ET has a lower resolution. Therefore, the combination of cryo-EM single particle technology, cryo-ET, and related biophysical and cell biology methods can achieve a comprehensive understanding of amyloid in the brain.
Professor Xu Yanhui pointed out that the rapid development of structural biology related technologies in recent years has provided powerful tools for structural biology research, and has promoted structural biology to enter an unprecedented stage of prosperity. However, our understanding of biomacromolecules is still limited, and a paradigm shift led by structural biology related technologies is needed. First,A well-characterized and homogeneous sample is the key to cryo-EM single-particle analysis。The extraction of well-characterized and abundant endogenous protein complexes from cells or tissues relies on antibodies with strong specificity and affinity on the one hand, and on the other handA large amount of cell or tissue material is required to meet several rounds of optimization in sample preparation。Second, the use of in vitro recombinant methods to obtain biomacromolecular complexes provides us with convenience for studying their structure and function, howeverWhether the complexes obtained by in vitro recombination represent their true physiological state needs to be further verified。Therefore, the study of biological macromolecules in complex life processes still requires the development of new technologies.
This review summarizes the development status, existing problems and future challenges of cryo-EM. Although cryo-EM can now help us obtain electron images of extraordinary quality, it is conducive to a clearer view of the morphology of various living molecules. However, there are still major challenges to be overcome in the future, such as the optimization of the preparation of endogenous biological samples, and the structural elucidation of complex and flexible biological macromolecules。Therefore, the combination of other existing technologies, structures**, artificial intelligence and the development of new technologies can help us meet new challenges.
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