Cryo‐electron Microscopy as a Tool for Drug Discovery in the Context of Integrative Structural Biology

2020 ◽  
pp. 613-632
Author(s):  
Sacha De Carlo ◽  
Hervé‐William Rémigy
Keyword(s):  
Electron Microscopy ◽  
Drug Discovery ◽  
Structural Biology ◽  
Cryo Electron Microscopy ◽  
Integrative Structural Biology

scholarly journals Analysis of the Dynamic Proteasome Structure by Cross-Linking Mass Spectrometry

Biomolecules ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 505
Author(s):  
Marta L. Mendes ◽  
Gunnar Dittmar
Keyword(s):  
Electron Microscopy ◽  
Mass Spectrometry ◽  
Structural Biology ◽  
26S Proteasome ◽  
Cross Linking ◽  
Macromolecular Complex ◽  
Dynamic Nature ◽  
Cryo Electron Microscopy ◽  
Integrative Structural Biology ◽  
Regulatory Particle

The 26S proteasome is a macromolecular complex that degrades proteins maintaining cell homeostasis; thus, determining its structure is a priority to understand its function. Although the 20S proteasome’s structure has been known for some years, the highly dynamic nature of the 19S regulatory particle has presented a challenge to structural biologists. Advances in cryo-electron microscopy (cryo-EM) made it possible to determine the structure of the 19S regulatory particle and showed at least seven different conformational states of the proteasome. However, there are still many questions to be answered. Cross-linking mass spectrometry (CLMS) is now routinely used in integrative structural biology studies, and it promises to take integrative structural biology to the next level, answering some of these questions.

Cryo-EM Is a Powerful Tool, But Helical Applications Can Have Pitfalls

Soft Matter ◽  
2021 ◽  
Author(s):  
Edward Egelman ◽  
Fengbin Wang
Keyword(s):  
Electron Microscopy ◽  
Structural Biology ◽  
Macromolecular Complexes ◽  
Atomic Structures ◽  
Cryo Electron Microscopy ◽  
Main Technique

In structural biology, cryo-electron microscopy (cryo-EM) has emerged as the main technique for determining the atomic structures of macromolecular complexes. This has largely been due to the introduction of direct...

scholarly journals Cryo-electron microscopy reveals informative details of GABAA receptor structural pharmacology: implications for drug discovery

2019 ◽  
Vol 7 (S3) ◽  
pp. S144-S144 ◽  
Author(s):  
Richard W. Olsen ◽  
A. Kerstin Lindemeyer ◽  
Martin Wallner ◽  
Xiaorun Li ◽  
Kevin W. Huynh ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Drug Discovery ◽  
Gabaa Receptor ◽  
Cryo Electron Microscopy

Drug discovery in the era of cryo-electron microscopy

2021 ◽  
Author(s):  
Michael J. Robertson ◽  
Justin G. Meyerowitz ◽  
Georgios Skiniotis
Keyword(s):  
Electron Microscopy ◽  
Drug Discovery ◽  
Cryo Electron Microscopy

scholarly journals Single-particle cryo-EM—How did it get here and where will it go

Science ◽  
2018 ◽  
Vol 361 (6405) ◽  
pp. 876-880 ◽  
Author(s):  
Yifan Cheng
Keyword(s):  
Electron Microscopy ◽  
Structural Biology ◽  
Single Particle ◽  
Electron Crystallography ◽  
The Past ◽  
Cryo Electron Microscopy ◽  
Technological Advances ◽  
The Future ◽  
Electron Cryotomography

Cryo–electron microscopy, or simply cryo-EM, refers mainly to three very different yet closely related techniques: electron crystallography, single-particle cryo-EM, and electron cryotomography. In the past few years, single-particle cryo-EM in particular has triggered a revolution in structural biology and has become a newly dominant discipline. This Review examines the fascinating story of its start and evolution over the past 40-plus years, delves into how and why the recent technological advances have been so groundbreaking, and briefly considers where the technique may be headed in the future.

scholarly journals Rapid high-resolution structure analysis of small, biotechnologically relevant enzymes by cryo-electron microscopy

2021 ◽  
Author(s):  
Nicole Dimos ◽  
Carl P.O. Helmer ◽  
Andrea M. Chanique ◽  
Markus C. Wahl ◽  
Robert Kourist ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
High Resolution ◽  
Structural Biology ◽  
Structure Analysis ◽  
Cryo Electron Microscopy ◽  
High Resolution Structure ◽  
Fast Development ◽  
Pharmaceutical Industries ◽  
Exquisite Specificity ◽  
Resolution Structure

Enzyme catalysis has emerged as a key technology for developing efficient, sustainable processes in the chemical, biotechnological and pharmaceutical industries. Plants provide large and diverse pools of biosynthetic enzymes that facilitate complex reactions, such as the formation of intricate terpene carbon skeletons, with exquisite specificity. High-resolution structural analysis of these enzymes is crucial to understand their mechanisms and modulate their properties by targeted engineering. Although cryo-electron microscopy (cryo-EM) has revolutionized structural biology, its applicability to high-resolution structure analysis of comparatively small enzymes is so far largely unexplored. Here, we show that cryo-EM can reveal the structures of ~120 kDa plant borneol dehydrogenases at or below 2 Å resolution, paving the way for the fast development of new biocatalysts that provide access to bioactive terpenes and terpenoids.

Uncovering the structures of modular polyketide synthases

2015 ◽  
Vol 32 (3) ◽  
pp. 436-453 ◽  
Author(s):  
Kira J. Weissman
Keyword(s):  
Electron Microscopy ◽  
Structural Biology ◽  
Structural Characterization ◽  
Small Angle ◽  
Single Particle ◽  
Polyketide Synthases ◽  
X Ray ◽  
X Ray Scattering ◽  
Cryo Electron Microscopy

This review covers a breakthrough in the structural biology of the gigantic modular polyketide synthases (PKS): the structural characterization of intact modules by single-particle cryo-electron microscopy and small-angle X-ray scattering.

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