Optical Control of the Actin Cytoskeleton

肌动蛋白细胞骨架的光学控制

• 批准号: 10736022
• 负责人: DIRK HARTWIG TRAUNER
• 金额: $ 32.72万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736022
• 关键词: Actins; Alkynes; Allosteric Site; Azides; Binding; Biological; Cancer cell line; Cardiac; Cell physiology; Cells; Cellular biology; Chemicals; Clinical; Collaborations; Communities; Complex; Cryoelectron Microscopy; Cytochalasin D; Cytochalasins; Cytoskeleton; Darkness; Development; Docking; Drug Targeting; Elongation Factor; F-Actin; Filament; G Actin; Glues; Goals; Grant; Halogens; Hela Cells; Human; Label; Length; Light; Location; Marine Toxins; Microglia; Molecular; Molecular Motors; Motor; Myosin S-2; Myosin Type II; Natural Products; Neoplasm Metastasis; Neurons; Oligodendroglia; Optics; Organelles; Parents; Pathway interactions; Play; Polymers; Porifera; Property; Proteins; Roentgen Rays; Role; Running; Structural Biologist; Structure; Structure-Activity Relationship; Therapeutic; Toxin; Tubulin; Visible Radiation; X-Ray Crystallography; Yeasts; analog; azobenzene; blebbistatin; cell motility; cost; cytotoxic; design; high throughput screening; improved; in silico; inhibitor; jasplakinolide; latrunculin A; latrunculin B; monomer; pharmacokinetics and pharmacodynamics; programs; rational design; redshift; small molecule; stem; structural biology; temporal measurement; tool; vasodilator-stimulated phosphoprotein

Project Summary/Abstract The goal of this project is the optical control of the actin cytoskeleton with photoswitchable molecules. These compounds target monomeric G-actin, polymeric F-actin, the nucleator complex Arp2/3, and the motor protein myosin II. Our probes aimed at F-actin and G-actin are derived from the natural products jasplakinolide, yielding opto-Jasp, cytochalasin D (opto-Chal), and latrunculin B (opto-Lat), respectively. The photoswitchable molecules for Arp2/3 stem from CK-666 (opto-CK) and the photoswitchable myosin 2 inhibitors from blebbistatin and similar compounds (opto-MI). We have already obtained significant preliminary results in a variety of cells (e.g. yeast, HeLa, neurons, oligodendrocytes, microglia). Our proposed program constitutes the continuation of our long-standing and successful program on optically controlling actin and tubulin, as well as associated motor proteins with photoswitchable small molecules. The close collaboration between a chemical biologist and a structural biologist will yield useful probes that are shared with the community and could form the basis of a new form of precision chemotherapeutics.

项目概要/摘要 该项目的目标是通过光开关对肌动蛋白细胞骨架进行光学控制 分子。这些化合物靶向单体 G-肌动蛋白、聚合 F-肌动蛋白、成核剂 复合体 Arp2/3 和运动蛋白肌球蛋白 II。我们针对 F-肌动蛋白和 G-肌动蛋白的探针是 源自天然产物 jasplakinolide，产生 opto-Jasp、细胞松弛素 D (opto-Chal)、 和 latrunculin B (opto-Lat) 分别。 Arp2/3 的光开关分子源自 CK-666 (opto-CK) 和来自 blebbistatin 的光开关肌球蛋白 2 抑制剂及类似药物 化合物（opto-MI）。我们已经在多个方面取得了重要的初步成果 细胞（例如酵母、HeLa、神经元、少突胶质细胞、小胶质细胞）。我们提出的计划包括 我们长期成功的光学控制肌动蛋白计划的延续 微管蛋白，以及具有光开关小分子的相关运动蛋白。关闭 化学生物学家和结构生物学家之间的合作将产生有用的探针 与社区共享，并可以构成新的精确形式的基础 化疗。

项目成果

Computational Exploration of the Mechanism of Critical Steps in the Biomimetic Synthesis of Preuisolactone A, and Discovery of New Ambimodal (5 + 2)/(4 + 2) Cycloadditions.

• DOI: 10.1021/jacs.1c01856
• 发表时间: 2021-04-22
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Hong Zhang;Ale;er J. E. Novak;er;Cooper S. Jamieson;Xiao;Shuming Chen;D. Trauner;K. Houk
• 通讯作者: K. Houk

Natural product anticipation through synthesis.

通过合成对天然产物进行预期。

• 发表时间: 2022-03
• 作者: Hetzler, Belinda E;Trauner, Dirk;Lawrence, Andrew L
• 通讯作者: Lawrence, Andrew L

A Biomimetic Synthesis Elucidates the Origin of Preuisolactone A.

仿生合成阐明了 Preuisolactone A 的起源。

• DOI: 10.1021/jacs.9b08892
• 发表时间: 2019-09-13
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Ale;er J. E. Novak;er;Claire E Grigglestone;D. Trauner
• 通讯作者: D. Trauner

Complex Natural Products Derived from Pyrogallols.

源自连苯三酚的复杂天然产品。

• 发表时间: 2022
• 作者: Novak, Alexander J E;Trauner, Dirk
• 通讯作者: Trauner, Dirk

Optical Manipulation of F-Actin with Photoswitchable Small Molecules.

利用光开关小分子对 F-肌动蛋白进行光学操作。

• DOI: 10.1021/jacs.9b12898
• 发表时间: 2020-05-20
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Borowiak M;Küllmer F;Gegenfurtner F;Peil S;Nasufovic V;Zahler S;Thorn-Seshold O;Trauner D;Arndt HD
• 通讯作者: Arndt HD