Crystal structure of Hck in complex with a Src family-selective tyrosine kinase inhibitor.

Abstract:

:The crystal structure of the autoinhibited form of Hck has been determined at 2.0 A resolution, in complex with a specific pyrazolo pyrimidine-type inhibitor, PP1. The activation segment, a key regulatory component of the catalytic domain, is unphosphorylated and is visualized in its entirety. Tyr-416, the site of activating autophosphorylation in the Src family kinases, is positioned such that access to the catalytic machinery is blocked. PP1 is bound at the ATP-binding site of the kinase, and a methylphenyl group on PP1 is inserted into an adjacent hydrophobic pocket. The enlargement of this pocket in autoinhibited Src kinases suggests a route toward the development of inhibitors that are specific for the inactive forms of these proteins.

journal_name

Mol Cell

journal_title

Molecular cell

authors

Schindler T,Sicheri F,Pico A,Gazit A,Levitzki A,Kuriyan J

doi

10.1016/s1097-2765(00)80357-3

subject

Has Abstract

pub_date

1999-05-01 00:00:00

pages

639-48

issue

5

eissn

1097-2765

issn

1097-4164

pii

S1097-2765(00)80357-3

journal_volume

3

pub_type

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