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-Structure paper
タイトル | Structure of Microtubule-Trapped Human Kinesin-5 and Its Mechanism of Inhibition Revealed Using Cryoelectron Microscopy. |
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ジャーナル・号・ページ | Structure, Vol. 28, Issue 4, Page 450-457.e5, Year 2020 |
掲載日 | 2020年4月7日 |
著者 | Alejandro Peña / Aaron Sweeney / Alexander D Cook / Julia Locke / Maya Topf / Carolyn A Moores / |
PubMed 要旨 | Kinesin-5 motors are vital mitotic spindle components, and disruption of their function perturbs cell division. We investigated the molecular mechanism of the human kinesin-5 inhibitor GSK-1, which ...Kinesin-5 motors are vital mitotic spindle components, and disruption of their function perturbs cell division. We investigated the molecular mechanism of the human kinesin-5 inhibitor GSK-1, which allosterically promotes tight microtubule binding. GSK-1 inhibits monomeric human kinesin-5 ATPase and microtubule gliding activities, and promotes the motor's microtubule stabilization activity. Using cryoelectron microscopy, we determined the 3D structure of the microtubule-bound motor-GSK-1 at 3.8 Å overall resolution. The structure reveals that GSK-1 stabilizes the microtubule binding surface of the motor in an ATP-like conformation, while destabilizing regions of the motor around the empty nucleotide binding pocket. Density corresponding to GSK-1 is located between helix-α4 and helix-α6 in the motor domain at its interface with the microtubule. Using a combination of difference mapping and protein-ligand docking, we characterized the kinesin-5-GSK-1 interaction and further validated this binding site using mutagenesis. This work opens up new avenues of investigation of kinesin inhibition and spindle perturbation. |
リンク | Structure / PubMed:32084356 / PubMed Central |
手法 | EM (らせん対称) |
解像度 | 3.8 - 6.1 Å |
構造データ | EMDB-10421: Human kinesin-5 motor domain in the GSK-1 state bound to microtubules EMDB-10422, PDB-6ta4: |
化合物 | ChemComp-G2P: ChemComp-MG: ChemComp-MZK: ChemComp-GTP: ChemComp-ANP: |
由来 |
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キーワード | CELL CYCLE / kinesin / microtubule / mitosis / inhibition / motor |