9F8G

Photostatin (photoswitchable azo-combretastatin) Z-PST27 bound to tubulin-DARPin D1 complex

これはPDB形式変換不可エントリーです。

9F8G の概要

• エントリーDOI: 10.2210/pdb9f8g/pdb
• 分子名称: Tubulin alpha-1B chain, Tubulin beta-2B chain, Designed Ankyrin Repeat Protein (DARPIN) D1, ... (8 entities in total)
• 機能のキーワード: tubulin polymerisation inhibitor, microtubule dynamics, antimitotics, photopharmacology, photoswitch, sensitisation, cell cycle
• 由来する生物種: Bos taurus (cattle); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 119706.20

構造登録者

Wranik, M.,Steinmetz, M.O. (登録日: 2024-05-06, 公開日: 2024-09-04)

主引用文献

Reynders, M.,Garscia, M.,Muller-Deku, A.,Wranik, M.,Krauskopf, K.,de la Osa de la Rosa, L.,Schaffer, K.,Jotten, A.,Rode, A.,Stierle, V.,Kraus, Y.,Baumgartner, B.,Ali, A.,Bubeneck, A.,Seal, T.,Steinmetz, M.O.,Paulitschke, P.,Thorn-Seshold, O.
A photo-SAR study of photoswitchable azobenzene tubulin-inhibiting antimitotics identifying a general method for near-quantitative photocontrol.
Chem Sci, 15:12301-12309, 2024

PubMed Abstract: Azobenzene analogues of the tubulin polymerisation inhibitor combretastatin A4 (PSTs) were previously developed to optically control microtubule dynamics in living systems, with subsecond response time and single-cell spatial precision, by reversible photoswitching of their bioactivity with near-UV/visible light. First-generation PSTs were sufficiently potent and photoswitchable for use in live cells and embryos. However, the link between their seconds-scale and hours-scale bioactivity remained untested. Furthermore, the scope for modifications to tune their photo-structure-activity-relationship or expand their function was unknown. Here, we used large-field-of-view, long-term tandem photoswitching/microscopy to reveal the temporal onset of cytostatic effects. We then synthesised a panel of novel PSTs exploring structural variations that tune photoresponse wavelengths and lipophilicity, identifying promising blue-shifted analogues that are better-compatible with GFP/YFP imaging. Taken together, these results can guide new design and applications for photoswitchable microtubule inhibitors. We also identified tolerated sites for linkers to attach functional cargos; and we tested fluorophores, aiming at RET isomerisation or reporter probes. Instead we found that these antennas greatly enhance long-wavelength single-photon photoisomerisation, by an as-yet un-explored mechanism, that can now drive general progress towards near-quantitative long-wavelength photoswitching of photopharmaceuticals in living systems, with minimal molecular redesign and broad scope.

PubMed: 39118608
DOI: 10.1039/d4sc03072a

実験手法

X-RAY DIFFRACTION (2.2 Å)