Structural basis of new allosteric inhibition in Kinesin spindle protein Eg5.
ACS Chem Biol
; 10(4): 1128-36, 2015 Apr 17.
Article
en En
| MEDLINE
| ID: mdl-25622007
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.
Texto completo:
1
Colección:
01-internacional
Asunto principal:
Sulfonamidas
/
Compuestos de Bifenilo
/
Cinesinas
Límite:
Humans
Idioma:
En
Revista:
ACS Chem Biol
Año:
2015
Tipo del documento:
Article
País de afiliación:
Japón