9f8g
Photostatin (photoswitchable azo-combretastatin) Z-PST27 bound to tubulin-DARPin D1 complex
Structural highlights
FunctionTBA1B_BOVIN Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain. Publication Abstract from PubMedAzobenzene 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 in situ 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. A photo-SAR study of photoswitchable azobenzene tubulin-inhibiting antimitotics identifying a general method for near-quantitative photocontrol.,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 MO, Paulitschke P, Thorn-Seshold O Chem Sci. 2024 Jul 2;15(31):12301-12309. doi: 10.1039/d4sc03072a. eCollection , 2024 Aug 7. PMID:39118608[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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