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-Structure paper
タイトル | The structural basis of force generation by the mitotic motor kinesin-5. |
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ジャーナル・号・ページ | J Biol Chem, Vol. 287, Issue 53, Page 44654-44666, Year 2012 |
掲載日 | 2012年12月28日 |
著者 | Adeline Goulet / William M Behnke-Parks / Charles V Sindelar / Jennifer Major / Steven S Rosenfeld / Carolyn A Moores / |
PubMed 要旨 | 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 ...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. |
リンク | J Biol Chem / PubMed:23135273 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 9.5 - 15.0 Å |
構造データ | EMDB-2077: Electron cryo-microscopy of microtubule-bound human kinesin-5 motor domain in AMPPNP state. EMDB-2078: Electron cryo-microscopy of microtubule-bound human kinesin-5 motor domain in rigor state EMDB-2079: EMDB-2080: EMDB-2081: EMDB-2152: |
化合物 | ChemComp-MG: ChemComp-GTP: ChemComp-GDP: ChemComp-TA1: ChemComp-ANP: |
由来 |
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キーワード | MOTOR PROTEIN / MICROTUBULE / MITOSIS / CANCER |