4AQW

Model of human kinesin-5 motor domain (1II6, 3HQD) and mammalian tubulin heterodimer (1JFF) docked into the 9.5-angstrom cryo-EM map of microtubule-bound kinesin-5 motor domain in the rigor state.

Summary for 4AQW

• Entry DOI: 10.2210/pdb4aqw/pdb
• Related: 1II6 1JFF 1Q0B 1SA0 1SA1 1TVK 1X88 1YRS 1Z2B 2FKY 2FL2 2FL6 2G1Q 2GM1 2UYI 2UYM 2WBE 2WOG 2X2R 2X7C 2X7D 2X7E 2XAE 2XRP 4A1Z 4A28 4A2T 4A50 4A51 4A5Y 4AP0 4AQV
• EMDB information: 2077 2078 2079 2080 2081
• Descriptor: TUBULIN ALPHA-1D CHAIN, TUBULIN BETA-2B CHAIN, KINESIN-LIKE PROTEIN KIF11, ... (7 entities in total)
• Functional Keywords: motor protein, microtubule, mitosis, cancer
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Cytoplasm, cytoskeleton : Q2HJ86 Q6B856; Cytoplasm : P52732
• Total number of polymer chains: 3
• Total formula weight: 143661.82

Authors

Goulet, A.,Behnke-Parks, W.M.,Sindelar, C.V.,Rosenfeld, S.S.,Moores, C.A. (deposition date: 2012-04-19, release date: 2012-11-21, Last modification date: 2024-05-08)

Primary citation

Goulet, A.,Behnke-Parks, W.M.,Sindelar, C.V.,Major, J.,Rosenfeld, S.S.,Moores, C.
The Structural Basis of Force Generation by the Mitotic Motor Kinesin-5.
J.Biol.Chem., 287:44654-, 2012

PubMed Abstract: Kinesin-5 is required for forming the bipolar spindle during mitosis. Its motor domain, which contains nucleotide and microtubule binding sites and mechanical elements to generate force, has evolved distinct properties for its spindle-based functions. In this study, we report subnanometer resolution cryoelectron microscopy reconstructions of microtubule-bound human kinesin-5 before and after nucleotide binding and combine this information with studies of the kinetics of nucleotide-induced neck linker and cover strand movement. These studies reveal coupled, nucleotide-dependent conformational changes that explain many of this motor's properties. We find that ATP binding induces a ratchet-like docking of the neck linker and simultaneous, parallel docking of the N-terminal cover strand. Loop L5, the binding site for allosteric inhibitors of kinesin-5, also undergoes a dramatic reorientation when ATP binds, suggesting that it is directly involved in controlling nucleotide binding. Our structures indicate that allosteric inhibitors of human kinesin-5, which are being developed as anti-cancer therapeutics, bind to a motor conformation that occurs in the course of normal function. However, due to evolutionarily defined sequence variations in L5, this conformation is not adopted by invertebrate kinesin-5s, explaining their resistance to drug inhibition. Together, our data reveal the precision with which the molecular mechanism of kinesin-5 motors has evolved for force generation.

PubMed: 23135273
DOI: 10.1074/JBC.M112.404228

Experimental method

ELECTRON MICROSCOPY (9.5 Å)