Structure of Microtubule-Trapped Human Kinesin-5 and Its Mechanism of Inhibition Revealed Using Cryoelectron Microscopy.
antimitotic
cryo-electron microscopy
image reconstruction
inhibitor
kinesin
microtubule
Journal
Structure (London, England : 1993)
ISSN: 1878-4186
Titre abrégé: Structure
Pays: United States
ID NLM: 101087697
Informations de publication
Date de publication:
07 04 2020
07 04 2020
Historique:
received:
04
10
2019
revised:
12
12
2019
accepted:
28
01
2020
pubmed:
23
2
2020
medline:
17
4
2021
entrez:
22
2
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32084356
pii: S0969-2126(20)30040-X
doi: 10.1016/j.str.2020.01.013
pmc: PMC7139217
pii:
doi:
Substances chimiques
KIF11 protein, human
0
Kinesins
EC 3.6.4.4
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
450-457.e5Subventions
Organisme : Wellcome Trust
ID : 202679/Z/16/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 209250/Z/17/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 206166/Z/17/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 208398/Z/17/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N009614/1
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Worldwide Cancer Research
ID : 16-0037
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0600084
Pays : United Kingdom
Commentaires et corrections
Type : ErratumIn
Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests The authors declare no competing interests.
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