5OV7
tubulin - rigosertib complex
Summary for 5OV7
| Entry DOI | 10.2210/pdb5ov7/pdb |
| Descriptor | Tubulin alpha-1B chain, N-[2-methoxy-5-({[(E)-2-(2,4,6-trimethoxyphenyl)ethenyl]sulfonyl}methyl)phenyl]glycine, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, ... (13 entities in total) |
| Functional Keywords | cell cycle, tubulin fold, cytoskeleton, microtubule |
| Biological source | Rattus norvegicus (Norway Rat) More |
| Cellular location | Cytoplasm, cytoskeleton: P81947 Q6B856 Golgi apparatus : P63043 |
| Total number of polymer chains | 6 |
| Total formula weight | 265881.68 |
| Authors | Menchon, G.,Prota, A.E.,Steinmetz, M.,Jost, M. (deposition date: 2017-08-28, release date: 2017-10-11, Last modification date: 2024-01-17) |
| Primary citation | Jost, M.,Chen, Y.,Gilbert, L.A.,Horlbeck, M.A.,Krenning, L.,Menchon, G.,Rai, A.,Cho, M.Y.,Stern, J.J.,Prota, A.E.,Kampmann, M.,Akhmanova, A.,Steinmetz, M.O.,Tanenbaum, M.E.,Weissman, J.S. Combined CRISPRi/a-Based Chemical Genetic Screens Reveal that Rigosertib Is a Microtubule-Destabilizing Agent. Mol. Cell, 68:210-223.e6, 2017 Cited by PubMed Abstract: Chemical libraries paired with phenotypic screens can now readily identify compounds with therapeutic potential. A central limitation to exploiting these compounds, however, has been in identifying their relevant cellular targets. Here, we present a two-tiered CRISPR-mediated chemical-genetic strategy for target identification: combined genome-wide knockdown and overexpression screening as well as focused, comparative chemical-genetic profiling. Application of these strategies to rigosertib, a drug in phase 3 clinical trials for high-risk myelodysplastic syndrome whose molecular target had remained controversial, pointed singularly to microtubules as rigosertib's target. We showed that rigosertib indeed directly binds to and destabilizes microtubules using cell biological, in vitro, and structural approaches. Finally, expression of tubulin with a structure-guided mutation in the rigosertib-binding pocket conferred resistance to rigosertib, establishing that rigosertib kills cancer cells by destabilizing microtubules. These results demonstrate the power of our chemical-genetic screening strategies for pinpointing the physiologically relevant targets of chemical agents. PubMed: 28985505DOI: 10.1016/j.molcel.2017.09.012 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.402 Å) |
Structure validation
Download full validation report
