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Three-dimensional structure of the tyrosine kinase c-Src
1Laboratory of Molecular Medicine, Children's Hospital, Boston, Massachusetts 02115, USA.
Nature
|February 13, 1997
Summary
The structure of inactive c-Src tyrosine kinase reveals how domain interactions lock it down. Cellular signals or mutations can disrupt these interactions, activating the kinase.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- c-Src tyrosine kinase is a crucial regulator of cellular processes.
- Dysregulation of c-Src is implicated in various cancers.
- Understanding c-Src regulation is key to developing targeted therapies.
Purpose of the Study:
- To determine the high-resolution structure of a large fragment of c-Src.
- To elucidate the molecular mechanisms underlying c-Src inactivation.
- To provide insights into c-Src activation pathways.
Main Methods:
- X-ray crystallography was used to determine the structure.
- The structure was resolved at 1.7 A resolution.
- The fragment included regulatory and kinase domains and the C-terminal tail.
Main Results:
- The determined structure represents a closed, inactive state of c-Src.
- Interactions between domains, including the phosphorylated tail and SH2 domain, stabilize this inactive conformation.
- This conformation disrupts the kinase active site and shields SH2/SH3 domain binding surfaces.
Conclusions:
- The structure reveals how c-Src is maintained in an inactive state.
- Cellular signals or mutations can disrupt these inhibitory interactions.
- This disruption leads to an open, active kinase conformation, facilitating downstream signaling.