Microtubule dynamics: moving toward a multi-scale approach

Hemmat, Mahya; Castle, Brian T.; Odde, David J.

doi:10.1016/j.ceb.2017.12.013

Cited by 20 publications

(19 citation statements)

References 51 publications

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“…This dynamic behavior is of paramount importance to their biological functions and is therefore highly regulated in cells by an intricate combination of the tubulin isotypes and posttranslational modifications, the chemical state of the nucleotide at the E site, the conformations of the tubulin dimer, the microtubule lattice, and many proteins binding to the dimers and to the microtubule itself. The dynamic behavior of tubulin and microtubules and its relationship to mechanical and biochemical processes have been studied by means of a variety of computational methods due to the vast range of timescales (from nanoseconds to minutes or even hours) and resolutions (from atomistic to coarse‐grained models) covered . These studies are providing an understanding of the mechanisms underlying microtubule behavior, from GTP hydrolysis to microtubule growth, shrinkage, and dynamic instability and the effects and functioning of associated proteins or drug binding .…”

Section: Tubulin As a Targetmentioning

confidence: 99%

Antitubulin sulfonamides: The successful combination of an established drug class and a multifaceted target

Vicente‐Blázquez

González

Álvarez

et al. 2018

Medicinal Research Reviews

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Tubulin, the microtubules and their dynamic behavior are amongst the most successful antitumor, antifungal, antiparasitic, and herbicidal drug targets. Sulfonamides are exemplary drugs with applications in the clinic, in veterinary and in the agrochemical industry. This review summarizes the actual state and recent progress of both fields looking from the double point of view of the target and its drugs, with special focus onto the structural aspects. The article starts with a brief description of tubulin structure and its dynamic assembly and disassembly into microtubules and other polymers. Posttranslational modifications and the many cellular means of regulating and modulating tubulin's biology are briefly presented in the tubulin code. Next, the structurally characterized drug binding sites, their occupying drugs and the effects they induce are described, emphasizing on the structural requirements for high potency, selectivity, and low toxicity. The second part starts with a summary of the favorable and highly tunable combination of physical-chemical and biological properties that render sulfonamides a prototypical example of privileged scaffolds with representatives in many therapeutic areas. A complete description of tubulin-binding sulfonamides is provided, covering the different species and drug sites. Some of the antimitotic sulfonamides have met with very successful Med Res Rev. 2019;39:775-830. wileyonlinelibrary.com/journal/med © 2018 Wiley Periodicals, Inc. | 775applications and others less so, thus illustrating the advances, limitations, and future perspectives of the field.All of them combine in a mechanism of action and a clinical outcome that conform efficient drugs. K E Y W O R D S molecular mechanisms, sulfonamides, tubulin binding drugs, tubulin binding sites 1 | INTRODUCTION Drugs targeting tubulin and the microtubules (tubulin binding drugs [TBDs]) are amongst the most successful antitumor, antifungal, antiparasitic, and herbicidal agents with applications in the clinic, in veterinary and in the agrochemical industry. Recently, the combination of computational methods, medicinal chemistry, biochemistry, structural biology, and cell biology is starting to unravel the intricacies of tubulin binding drugs and of the microtubules themselves, thus paving the way towards new and better TBDs. New methodological advances such as the high resolution cryo-electron microscopy, the imaging of individual microtubule dynamics, and the achievement of recombinant tubulin, altogether with more established methodologies for the study of the microtubules have combined to provide a sharper view of the structure and function of these essential cell components and their interactions with clinically important drugs. The sulfonamides are a prototypical example of privileged scaffolds, with representatives in many therapeutic areas, due to a combination of favorable and highly tunable physical-chemical and biological properties. The early discovery of the dinitroaniline herbicides, and mainly the seminal discovery o...

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Section: Tubulin As a Targetmentioning

confidence: 99%

Antitubulin sulfonamides: The successful combination of an established drug class and a multifaceted target

Vicente‐Blázquez

González

Álvarez

et al. 2018

Medicinal Research Reviews

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“…In the last decade, advances in high-resolution techniques have shed new light on how the dynamic behavior of microtubules is modulated (as reviewed in 37 ). Here, we present new software, MTrack, which automatically identifies and tracks dynamic microtubules with subpixel resolution and provides automatic data interpretation and statistics.…”

Section: Discussionmentioning

confidence: 99%

MTrack: Automated Detection, Tracking, and Analysis of Dynamic Microtubules

Kapoor

Hirst

Hentschel

et al. 2019

Sci Rep

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Microtubules are polar, dynamic filaments fundamental to many cellular processes. In vitro reconstitution approaches with purified tubulin are essential to elucidate different aspects of microtubule behavior. To date, deriving data from fluorescence microscopy images by manually creating and analyzing kymographs is still commonplace. Here, we present MTrack, implemented as a plug-in for the open-source platform Fiji, which automatically identifies and tracks dynamic microtubules with sub-pixel resolution using advanced objection recognition. MTrack provides automatic data interpretation yielding relevant parameters of microtubule dynamic instability together with population statistics. The application of our software produces unbiased and comparable quantitative datasets in a fully automated fashion. This helps the experimentalist to achieve higher reproducibility at higher throughput on a user-friendly platform. We use simulated data and real data to benchmark our algorithm and show that it reliably detects, tracks, and analyzes dynamic microtubules and achieves sub-pixel precision even at low signal-to-noise ratios.

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“…In particular, the role of GTP hydrolysis, which leads to conformational changes in tubulin and is believed to trigger filament disassembly, and the impact of various microtubule associated proteins are still 4 elusive. The microtubule instability has been investigated with dimer-scaled lattice models which share many common features [17][18][19][20][21][22][23]. A microtubule is represented by a helical lattice composed of thirteen protofilaments, as shown in Fig.…”

Section: Cytoskeletonmentioning

confidence: 99%

Minimal coarse-grained models for molecular self-organisation in biology

Hafner

Krausser

Šarić

2019

Current Opinion in Structural Biology

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The molecular machinery of life is largely created via self-organisation of individual molecules into functional assemblies. Minimal coarse-grained models, where a whole macromolecule is represented by a small number of particles, can be of great value in identifying the main driving forces behind self-organisation in cell biology. Such models can incorporate data from both molecular and continuum scales, and their results can be directly compared to experiments. Here we review the state of the art of models for studying the formation and biological function of macromolecular assemblies in cells. We outline the key ingredients of each model and their main findings. We illustrate the contribution of this class of simulations to identifying the physical mechanisms behind life and diseases, and discuss their future developments. IntroductionSelf-assembly of individual molecules into large-scale functional structures generates the molecular machinery of life [1]. Such processes underlie the formation of cell membranes, protein filaments and networks, and drive the formation of three-dimensional genome structures. Many of these assemblies, such as protein filaments and lattices, also function as efficient nanomachines that enable cells to sense, move, divide, and transport materials in and out of the cell [2]. To sustain life, the formation of macromolecular assemblies needs to *

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Microtubule dynamics: moving toward a multi-scale approach

Cited by 20 publications

References 51 publications

Antitubulin sulfonamides: The successful combination of an established drug class and a multifaceted target

Antitubulin sulfonamides: The successful combination of an established drug class and a multifaceted target

MTrack: Automated Detection, Tracking, and Analysis of Dynamic Microtubules

Minimal coarse-grained models for molecular self-organisation in biology

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