3KEN

Human Eg5 in complex with S-trityl-L-cysteine

Summary for 3KEN

• Entry DOI: 10.2210/pdb3ken/pdb
• Related: 1II6 1X88 2WOG 3HQD
• Descriptor: Kinesin-like protein KIF11, ADENOSINE-5'-DIPHOSPHATE, S-TRITYL-L-CYSTEINE, ... (6 entities in total)
• Functional Keywords: cell cycle, kinesin-inhibitor complex, motor domain, l5 loop, atp-binding, cell division, coiled coil, microtubule, mitosis, motor protein, nucleotide-binding, phosphoprotein
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P52732
• Total number of polymer chains: 1
• Total formula weight: 42042.83

Authors

Parke, C.L.,Wojcik, E.J.,Kim, S.,Worthylake, D.K. (deposition date: 2009-10-26, release date: 2010-03-16, Last modification date: 2023-09-06)

Primary citation

Kim, E.D.,Buckley, R.,Learman, S.,Richard, J.,Parke, C.,Worthylake, D.K.,Wojcik, E.J.,Walker, R.A.,Kim, S.
Allosteric drug discrimination is coupled to mechanochemical changes in the kinesin-5 motor core.
J.Biol.Chem., 285:18650-18661, 2010

PubMed 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.

PubMed: 20299460
DOI: 10.1074/jbc.M109.092072

Experimental method

X-RAY DIFFRACTION (2.5 Å)