Academic Press Current Approaches to Cryo-electron Microscopy (Volume 223) (Progress in Molecular Biology and Translational Science, Volume 223)

Cryo-electron microscopy (cryo-EM) has emerged as a transformative technique in structural biology, driving an exponential increase in the number of structures deposited in the Protein Data Bank. Current workflows now routinely achieve the near-atomic resolution essential for understanding the molecular pathology of neurodegenerative and metabolic disorders. This provides a comprehensive overview of the field, tracing the evolution from early structural studies to modern pipelines powered by deep-learning algorithms for helical reconstruction. We address the persistent bottleneck of sample preparation, detailing the physical challenges of fibril clumping and interfacial adsorption, alongside emerging solutions to these problems. Furthermore, we examine the complexities of structural polymorphism, discussing how environmental factors and seeding drive conformational diversity and how this heterogeneity impacts biochemical assays. Finally, we highlight the translational value of these high-resolution maps, demonstrating how they enable the rational, structure-based design of peptide inhibitors and small molecules capable of disaggregating pathogenic fibrils. Reviews cryo-EM yields near-atomic structures that advance neurodegenerative/metabolic disease understanding and enable drug design Provides information on deep-learning AI accelerates structure determination through image processing, map enhancement, and model building Assesses key challenges and opportunities including sample prep bottlenecks, polymorphism, and using high-res maps to design inhibitors that disaggregate fibrils