title: Structural basis of new allosteric inhibition in Kinesin spindle protein Eg5.
abstract: Kinesin 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 α4/α6 allosteric pocket 15 Å from the ATP-binding pocket, which differs from conventional allosteric inhibitors that bind to the allosteric L5/α2/α3 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.
authors.affiliation: †Department of Physical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan.
authors.forename: Hideshi
authors.initials: H
authors.lastname: Yokoyama
authors.affiliation: ‡Center for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan.
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Sawada
authors.affiliation: †Department of Physical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan.
authors.forename: Shiori
authors.initials: S
authors.lastname: Katoh
authors.affiliation: ‡Center for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsuno
authors.affiliation: ‡Center for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan.
authors.forename: Naohisa
authors.initials: N
authors.lastname: Ogo
authors.affiliation: †Department of Physical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Ishikawa
authors.affiliation: †Department of Physical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hashimoto
authors.affiliation: †Department of Physical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fujii
authors.affiliation: ‡Center for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Asai
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism; D008958:Models, Molecular; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D013449:Sulfonamides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D014443:Tyrosine / Q000378:metabolism
chemical_list: D001713:Biphenyl Compounds; C470243:KIF11 protein, human; C000607181:PVZB1194; D013449:Sulfonamides; D014443:Tyrosine; D000255:Adenosine Triphosphate; D016547:Kinesins