Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.6.4.4 (kinesin)
 5,033 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The realization that many essential functions of living cells are performed by nanoscale motors consisting of protein complexes has given rise to an intense effort to understand their mechanisms. Considerable progress has been made in the past two years by a combination of biophysical techniques and theoretical analysis. Single-molecule studies have played a spectacular role for a variety of motors including kinesin, myosin, and polymerases. The understanding of F(1)-ATPase, the smallest biomolecular rotary motor, has made particular progress by the interplay of experimental and theoretical studies; the latter have provided information not available from experiment.
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PMID:Biomolecular motors: the F1-ATPase paradigm. 1509 41

The final goal of our group is to establish the missing link between chemical reaction and mechanical event in molecular motors. To achieve this, we have developed advanced versions of conventional optical microscopes and applied them into single-molecule techniques. In this chapter we present two studies: one is about the kinesin-microtubule system and the other F(1)-ATPase. These techniques are applicable to other molecular machines, hopefully in more sophisticated ways, and we hope to investigate this in future studies.
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PMID:Molecular bio-motors in living cells. 2023 91

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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PMID:Allosteric drug discrimination is coupled to mechanochemical changes in the kinesin-5 motor core. 2029 60

Molecular motors such as kinesin, myosin, and F(1)-ATPase are responsible for many important cellular processes. These motor proteins exhibit nanometer-scale, stepwise movements on micro- to millisecond timescales. So far, methods developed to measure these small and fast movements with high spatial and temporal resolution require relatively complicated experimental systems. Here, we describe a simple dark-field imaging system that employs objective-type evanescent illumination to selectively illuminate a thin layer on the coverslip and thus yield images with high signal/noise ratios. Only by substituting the dichroic mirror in conventional objective-type total internal reflection fluorescence microscope with a perforated mirror, were nanometer spatial precision and microsecond temporal resolution simultaneously achieved. This system was applied to the study of the rotary mechanism of F(1)-ATPase. The fluctuation of a gold nanoparticle attached to the gamma-subunit during catalytic dwell and the stepping motion during torque generation were successfully visualized with 9.1-mus temporal resolution. Because of the simple optics, this system will be applicable to various biophysical studies requiring high spatial and temporal resolution in vitro and also in vivo.
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PMID:Simple dark-field microscopy with nanometer spatial precision and microsecond temporal resolution. 2044 66

Many single-molecule experiments for molecular motors comprise not only the motor but also large probe particles coupled to it. The theoretical analysis of these assays, however, often takes into account only the degrees of freedom representing the motor. We present a coarse-graining method that maps a model comprising two coupled degrees of freedom which represent motor and probe particle to such an effective one-particle model by eliminating the dynamics of the probe particle in a thermodynamically and dynamically consistent way. The coarse-grained rates obey a local detailed balance condition and reproduce the net currents. Moreover, the average entropy production as well as the thermodynamic efficiency is invariant under this coarse-graining procedure. Our analysis reveals that only by assuming unrealistically fast probe particles, the coarse-grained transition rates coincide with the transition rates of the traditionally used one-particle motor models. Additionally, we find that for multicyclic motors the stall force can depend on the probe size. We apply this coarse-graining method to specific case studies of the F(1)-ATPase and the kinesin motor.
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PMID:Effective rates from thermodynamically consistent coarse-graining of models for molecular motors with probe particles. 2576 33