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Kinesin spindle protein Eg5 in complex with ATP-competitive inhibitor PVZB1194Kinesin spindle protein Eg5 in complex with ATP-competitive inhibitor PVZB1194
Structural highlights
DiseaseKIF11_HUMAN Defects in KIF11 are the cause of microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR) [MIM:152950. An autosomal dominant disorder that involves an overlapping but variable spectrum of central nervous system and ocular developmental anomalies. Microcephaly ranges from mild to severe and is often associated with mild to moderate developmental delay and a characteristic facial phenotype with upslanting palpebral fissures, broad nose with rounded tip, long philtrum with thin upper lip, prominent chin, and prominent ears. Chorioretinopathy is the most common eye abnormality, but retinal folds, microphthalmia, and myopic and hypermetropic astigmatism have also been reported, and some individuals have no overt ocular phenotype. Congenital lymphedema, when present, is typically confined to the dorsa of the feet, and lymphoscintigraphy reveals the absence of radioactive isotope uptake from the webspaces between the toes.[1] FunctionKIF11_HUMAN Motor protein required for establishing a bipolar spindle. Blocking of KIF11 prevents centrosome migration and arrest cells in mitosis with monoastral microtubule arrays.[2] Publication Abstract from PubMedKinesin spindle protein Eg5 is a target for anticancer therapies, and small molecule inhibitors of its ATPase activity have been developed. We herein report for the first time the crystal structure of and biochemical studies on the Eg5 motor domain in complex with a new type of allosteric inhibitor. The biphenyl-type inhibitor PVZB1194 binds to the alpha4/alpha6 allosteric pocket 15 A from the ATP-binding pocket, which differs from conventional allosteric inhibitors that bind to the allosteric L5/alpha2/alpha3 pocket of Eg5. Binding of the inhibitor is involved in the neck-linker conformation and also causes conformational changes around the ATP-binding pocket through Tyr104 to affect the interaction of ATP with the pocket. This structure provides useful information for the development of novel types of allosteric drugs as well as a novel insight into the molecular mechanism responsible for regulating the motor activity of kinesins. Structural basis of new allosteric inhibition in Kinesin spindle protein eg5.,Yokoyama H, Sawada J, Katoh S, Matsuno K, Ogo N, Ishikawa Y, Hashimoto H, Fujii S, Asai A ACS Chem Biol. 2015 Apr 17;10(4):1128-36. doi: 10.1021/cb500939x. Epub 2015 Feb, 3. PMID:25622007[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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