Research output: Contribution to journal › Article › peer-review
Thomas S. Randall, Yan Y. Yip, Daynea J. Wallock-Richards, Karin Pfisterer, Anneri Sanger, Weronika Ficek, Roberto A. Steiner, Andrew J. Beavil, Maddy Parsons, Mark P. Dodding
Original language | English |
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Pages (from-to) | 13738-13743 |
Number of pages | 6 |
Journal | Proceedings of the National Academy of Sciences of the United States of America |
Volume | 114 |
Issue number | 52 |
Early online date | 11 Dec 2017 |
DOIs | |
Accepted/In press | 21 Nov 2017 |
E-pub ahead of print | 11 Dec 2017 |
Published | 26 Dec 2017 |
Additional links |
A small molecule activator_RANDALL_Firstonline11December2017_GREEN AAM
A_small_molecule_activator_RANDALL_Firstonline11December2017_GREEN_AAM.pdf, 3.15 MB, application/pdf
Uploaded date:09 May 2018
Version:Accepted author manuscript
The microtubule motor kinesin-1 interacts via its cargo-binding domain with both microtubules and organelles, and hence plays an important role in controlling organelle transport and microtubule dynamics. In the absence of cargo, kinesin-1 is found in an autoinhibited conformation. The molecular basis of how cargo engagement affects the balance between kinesin-1's active and inactive conformations and roles in microtubule dynamics and organelle transport is not well understood. Here we describe the discovery of kinesore, a small molecule that in vitro inhibits kinesin-1 interactions with short linear peptide motifs found in organelle-specific cargo adaptors, yet activates kinesin-1's function of controlling microtubule dynamics in cells, demonstrating that these functions are mechanistically coupled. We establish a proof-of-concept that a microtubule motor-cargo interface and associated autoregulatory mechanism can be manipulated using a small molecule, and define a target for the modulation of microtubule dynamics.
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