Cryo-EM as a powerful tool for drug discovery

Drie, John H. Van; Tong, Liang

doi:10.1016/j.bmcl.2020.127524

Cited by 61 publications

(41 citation statements)

References 117 publications

(120 reference statements)

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“…The activation of the “master switch” leads to suppression of glucose production in the liver and also contributes to glucose uptake into skeletal muscle [ 31 ]. According to Van Drie & Tong [ 33 ]; Cryogenic Electron Microscopy (cryo-EM) is a powerful novel technology not only for determining mechanism of action of known drugs but also for the development of brand-new compounds. Thus, a detailed structural study utilizing the latest technology such as cryo-EM is of the essence.…”

Section: Discussion and Recommendationsmentioning

confidence: 99%

The use of metformin as an add-on therapy to insulin in the treatment of poorly controlled type 1 diabetes mellitus in adolescents

et al. 2021

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The aim of this integrative literature review was to evaluate the efficacy and safety of Metformin as an add-on therapy to insulin in poorly controlled overweight adolescents with type 1 diabetes mellitus. The research problem centered on providing optimum disease management during the most critical growth period and reducing the potential for cardiovascular-related morbidity and mortality in the future. The findings suggested that Metformin, in conjunction with insulin therapy, helped patients to achieve better metabolic control. The quality of metabolic control varied between studies according to differences in study design, exclusion and inclusion criteria, and methods. Adjunctive Metformin therapy has a positive effect on diabetes management, treatment, and prevention of cardiovascular-related complications with a minimal risk of side effects. Suggestions for further exploration of the research results and clinical implications are included in the review.

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Section: Discussion and Recommendationsmentioning

confidence: 99%

The use of metformin as an add-on therapy to insulin in the treatment of poorly controlled type 1 diabetes mellitus in adolescents

et al. 2021

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“…As previously mentioned, the Pascal group crystallised four of the six domains of PARP1 [ 34 ] ( Figure 1 B); although a full-length structure has not yet been obtained. Perhaps the “resolution revolution” that cryo-EM is currently undergoing may provide a solution for this problem [ 151 , 152 , 153 ]. Recently the first full-length cryo-EM structure of a PARP enzyme was published.…”

Section: Parp Hpf1 and Nucleosome Remodellingmentioning

confidence: 99%

PARP Power: A Structural Perspective on PARP1, PARP2, and PARP3 in DNA Damage Repair and Nucleosome Remodelling

Beek

McClay

Patel

et al. 2021

IJMS

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Poly (ADP-ribose) polymerases (PARP) 1-3 are well-known multi-domain enzymes, catalysing the covalent modification of proteins, DNA, and themselves. They attach mono- or poly-ADP-ribose to targets using NAD+ as a substrate. Poly-ADP-ribosylation (PARylation) is central to the important functions of PARP enzymes in the DNA damage response and nucleosome remodelling. Activation of PARP happens through DNA binding via zinc fingers and/or the WGR domain. Modulation of their activity using PARP inhibitors occupying the NAD+ binding site has proven successful in cancer therapies. For decades, studies set out to elucidate their full-length molecular structure and activation mechanism. In the last five years, significant advances have progressed the structural and functional understanding of PARP1-3, such as understanding allosteric activation via inter-domain contacts, how PARP senses damaged DNA in the crowded nucleus, and the complementary role of histone PARylation factor 1 in modulating the active site of PARP. Here, we review these advances together with the versatility of PARP domains involved in DNA binding, the targets and shape of PARylation and the role of PARPs in nucleosome remodelling.

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“…Cryo-electron microscopy (cryo-EM) came up as an alternative to X-ray crystallography. Although very expensive and until recently low resolution, it can be applied to all types of samples in a near-native state [ 22 , 26 ], and it has been the technique of choice to study the structure of the 19S proteasome activator. In the late 2000s, two groups reported low-resolution structures of the 26S proteasome from Drosophila and Schizosaccharomyces pombe, respectively [ 27 , 28 ].…”

Section: Solving the Structure Of The Proteasomementioning

confidence: 99%

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

Mendes

Dittmar

2021

Biomolecules

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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.

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Cryo-EM as a powerful tool for drug discovery

Abstract: Graphical abstract

Cited by 61 publications

References 117 publications

The use of metformin as an add-on therapy to insulin in the treatment of poorly controlled type 1 diabetes mellitus in adolescents

The use of metformin as an add-on therapy to insulin in the treatment of poorly controlled type 1 diabetes mellitus in adolescents

PARP Power: A Structural Perspective on PARP1, PARP2, and PARP3 in DNA Damage Repair and Nucleosome Remodelling

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

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