ArticleThe Journal of biological chemistry2010
Allosteric drug discrimination is coupled to mechanochemical changes in the kinesin-5 motor core.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 49 citations in OpenAlex.
- Skeletal rearrangement in Biginelli reaction for the synthesis of chromenoquinoline fused spirohydantoins and their in silico cytotoxicity study.Scientific reports · 2026Article
- Molecular Dynamics Simulations Provide Further Insights into the Allosteric Regulation of the Kinesin-5 Motor Domain by Loop 5.Journal of chemical information and modeling · 2026Article
- L-proline HMolecular diversity · 2025Article
- Article
- Drug resistance dependent on allostery: A P-loop rigor Eg5 mutant exhibits resistance to allosteric inhibition by STLC.Frontiers in oncology · 2022Article
- Mechanisms by Which Kinesin-5 Motors Perform Their Multiple Intracellular Functions.International journal of molecular sciences · 2021Review
- Synthesis, cytotoxic assessment, and molecular docking studies of 2,6-diaryl-substituted pyridine and 3,4- dihydropyrimidine-2(1H)-one scaffolds.Turkish journal of chemistry · 2020Article
- Small molecule allosteric uncoupling of microtubule depolymerase activity from motility in human Kinesin-5 during mitotic spindle assembly.Scientific reports · 2019Article
- AntiproliferativeMolecules (Basel, Switzerland) · 2019Article
- Insights into the Molecular Mechanisms of Eg5 Inhibition by (+)-Morelloflavone.Pharmaceuticals (Basel, Switzerland) · 2019Article
- Src family kinase phosphorylation of the motor domain of the human kinesin-5, Eg5.Cytoskeleton (Hoboken, N.J.) · 2017Article
- Novel Allosteric Pathway of Eg5 Regulation Identified through Multivariate Statistical Analysis of Hydrogen-Exchange Mass Spectrometry (HX-MS) Ligand Screening Data.Molecular & cellular proteomics : MCP · 2017Article
- Allostery Wiring Map for Kinesin Energy Transduction and Its Evolution.The Journal of biological chemistry · 2016Article
- Review: Mechanochemistry of the kinesin-1 ATPase.Biopolymers · 2016Review
- Niche-Based Screening in Multiple Myeloma Identifies a Kinesin-5 Inhibitor with Improved Selectivity over Hematopoietic Progenitors.Cell reports · 2015Article
- Kinesin-5 allosteric inhibitors uncouple the dynamics of nucleotide, microtubule, and neck-linker binding sites.Biophysical journal · 2014Article
- Small molecule screen for candidate antimalarials targeting Plasmodium Kinesin-5.The Journal of biological chemistry · 2014Article
- Comprehensive structural model of the mechanochemical cycle of a mitotic motor highlights molecular adaptations in the kinesin family.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Mechanism and regulation of kinesin-5, an essential motor for the mitotic spindle.Biology of the cell · 2014Review
- Review
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
Essential in mitosis, the human Kinesin-5 protein is a target for >80 classes of allosteric compounds that bind to a surface-exposed site formed by the L5 loop. Not established is why there are differing efficacies in drug inhibition. Here we compare the ligand-bound states of two L5-directed inhibitors against 15 Kinesin-5 mutants by ATPase assays and IR spectroscopy. Biochemical kinetics uncovers functional differences between individual residues at the N or C termini of the L5 loop. Infrared evaluation of solution structures and multivariate analysis of the vibrational spectra reveal that mutation and/or ligand binding not only can remodel the allosteric binding surface but also can transmit long range effects. Changes in L5-localized 3(10) helix and disordered content, regardless of substitution or drug potency, are experimentally detected. Principal component analysis couples these local structural events to two types of rearrangements in beta-sheet hydrogen bonding. These transformations in beta-sheet contacts are correlated with inhibitory drug response and are corroborated by wild type Kinesin-5 crystal structures. Despite considerable evolutionary divergence, our data directly support a theorized conserved element for long distance mechanochemical coupling in kinesin, myosin, and F(1)-ATPase. These findings also suggest that these relatively rapid IR approaches can provide structural biomarkers for clinical determination of drug sensitivity and drug efficacy in nucleotide triphosphatases.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.